MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Combinatorial Chemistry and High Throughput Screening' source. Sat, 20 Mar 2010 15:57:53 +0100 http://www.medworm.com/index.php?rid=3379505&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20230370%26dopt%3DAbstract Authors: Wang Y, Bajorath J Fingerprint representations of molecular structure and properties were among the first computational tools for similarity searching and are widely applied to this date, which is in part due to their computational efficiency and ease-of-use. Moreover, despite their simplicity, 2D molecular fingerprints have been surprisingly successful in identifying novel active compounds. However, properly applying 2D fingerprint representations and similarity metrics in the search for active molecules is much more complicated than one might assume. For example, no generally applicable similarity functions and threshold values exist that reliably indicate a level of molecular similarity that results in similar biological activity. Furthermore, fingerprint search calculation... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3379505 Mon, 01 Mar 2010 00:00:00 +0100 3379505 http://www.medworm.com/index.php?rid=3379504&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20230371%26dopt%3DAbstract Authors: Järvinen PP, Fallarero A, Gupta S, Mohan GC, Hatakka AI, Vuorela PM The aim of this study was to screen for acetylcholinesterase (AChE) inhibitors from a large chemical library of commercially available compounds. For this purpose, the Ellman's reaction based assay was miniaturized into 384-well plate format, and two modifications of the kinetic protocol were studied with the aim of developing a rapid screening platform that could ensure high efficiency in finding true hits. It was proven that when starting the kinetic reaction by addition of the substrate, better assay performance was achieved and more practical benefits obtained. Using the optimized automated protocol, a chemical library of 56,320 compounds was screened. A total of 350 positive hits were identified and ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3379504 Mon, 01 Mar 2010 00:00:00 +0100 3379504 http://www.medworm.com/index.php?rid=3379503&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20230373%26dopt%3DAbstract Authors: Min L, Hui X In the family of biologically active heterocyclic templates, quinoxalines, quinoxalinones, and quinoxalinols have received much attention owing to a wide range of their biological activities. As a consequence, approaches to the combinatorial synthesis of these compounds were surveyed, and this review discusses the solid-phase, solution-phase, solvent-free, and microwave-assisted parallel synthesis of quinoxalines, quinoxalinones, and quinoxalinols. PMID: 20230373 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3379503 Mon, 01 Mar 2010 00:00:00 +0100 3379503 http://www.medworm.com/index.php?rid=3379502&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20230372%26dopt%3DAbstract Authors: Carter MD, Phelan VV, Sandlin RD, Bachmann BO, Wright DW The growing drug resistance of Plasmodia spp. to current antimalarial agents in the quinine and artemisinin families further asserts the need for novel drug classes to combat malaria infection. One approach to the discovery of new antimalarials is the screening of natural product extracts for activity against the formation of hemozoin, a biomineral essential to parasite survival. By mimicking the in vivo lipid-water interface at which native hemozoin is found, hemozoin can be synthesized outside the parasite. In this work, a variety of lipophilic mediators was used to determine the optimal platform for in vitro hemozoin formation and then tested for efficacy in preliminary screens containing crude natural product extract... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3379502 Mon, 01 Mar 2010 00:00:00 +0100 3379502 http://www.medworm.com/index.php?rid=3284391&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20156143%26dopt%3DAbstract Authors: Yuan K, Lei Y, Huang C Pharmaceutical companies are being forced by market competition to find new ways of novel drug target screening instead of traditional methods. The completion of human genome sequencing has provided a flood of new information that might help identify potential drug targets. Finding promising novel drug targets from this flood of information remains challenging. For de novo target screening, the interactions between a drug and cellular components must be comprehensively characterized for better understanding of the pharmacological activities of the drug. The multidisciplinary chemistry-based functional proteomics can be used to elucidate the interactions, because it provides a method to focus initial new drug target identification towards proteins that ar... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3284391 Sat, 16 Jan 2010 00:00:00 +0100 3284391 http://www.medworm.com/index.php?rid=3284389&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20156144%26dopt%3DAbstract Authors: Chen Z, Liu G, Chen M, Chen X, Wu M, Chen X DNA is a valid drug target for development of target-based therapeutics against cancer. Screening DNA-targeted anticancer drugs is a key process for the research and development of new anticancer drugs. The traditional anticancer drug screening methods, including animal experiments and cell-based screening assays, have unavoidable drawbacks. In this contribution, the new instrument-based screening assay for DNA-targeted anticancer drugs in vitro using resonance light scattering (RLS) technique was proposed. The experiments suggested that the increment of RLS intensity was directly proportional to the antitumor effect of anticancer drugs. Therefore, it was intuitive to obtain the sequence of the antitumor activity of four anticancer d... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3284389 Sat, 16 Jan 2010 00:00:00 +0100 3284389 http://www.medworm.com/index.php?rid=3284386&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20156145%26dopt%3DAbstract This article reviews the wide application field of magnetic, gold, silver, semiconductor and other nanoparticles in high throughput bioassays. Also, the versatility of the detection systems described shows that NPs are useful alternatives to fluorescent dyes, which are often used in these assays. PMID: 20156145 [PubMed - as supplied by publisher] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3284386 Sat, 16 Jan 2010 00:00:00 +0100 3284386 http://www.medworm.com/index.php?rid=3284385&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20156146%26dopt%3DAbstract Authors: Abdallah R, Grenouillet P, Vriamont N, Riant O, de Bellefon C A library of 117 ligands was combined with three transition metals Ru, Rh and Ir and screened with three different operating conditions for the asymmetric H-transfer reduction of acetophenone into phenylethanol. The combinatorial approach was based on evolution of a first library containing 60 ligands. For the evolution, operators such as replication, regression, cross-over and mutation were used. The study was performed with a XYZ robot and fast chiral GC analysis. Over only 4 generations, the average targeted criterion, enantioselectivity, was increased from 20% to ca. 80% for the 4rth generation. The best results provided enantiomeric excess up to 93%. PMID: 20156146 [PubMed - as supplied by publisher] (Sourc... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3284385 Sat, 16 Jan 2010 00:00:00 +0100 3284385 http://www.medworm.com/index.php?rid=3284384&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20156147%26dopt%3DAbstract Authors: Clausell-Tormos J, Griffiths AD, Merten CA Cell-based assays for the inhibition of viral infections most commonly couple a positive signal (e.g., an increase in fluorescence) to the infection itself and not to its inhibition. When performing drug screens, compounds decreasing the signal are therefore considered as putative inhibitors. However, this approach can cause the selection of many false positives, since, for example, both killing of the host cell and inhibiting viral cell-entry results in the same signal. Using a model system based on murine leukemia virus (MLV) particles pseudotyped with the G-protein of vesicular stomatitis virus (VSV-G), we have developed generic assays coupling a positive readout to the inhibition of viral transduction. Consequently, the system fav... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3284384 Sat, 16 Jan 2010 00:00:00 +0100 3284384 http://www.medworm.com/index.php?rid=3284383&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20156148%26dopt%3DAbstract Authors: Christ TN, Deweese KA, Woodyer RD Improvement of the one-step production of L-ribose from ribitol using a recombinant Escherichia coli is described. The gene encoding the enzyme mannitol-1-dehydrogenase (MDH) from Apium graveolens has previously been codon-optimized, cloned into the constitutive pZuc10 vector, and expressed in E. coli. This MDH catalyzes the NAD-dependent conversion of mannitol to D-mannose and has the ability to convert several polyols to their L-sugar counterparts, including ribitol to L-ribose. Here, three rounds of directed evolution using libraries generated through error-prone PCR and screened using a dinitrosalicylate reagent were prepared. Mutants were selected for improved conversion of L-ribose, and the best mutant was isolated by combining two round... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3284383 Sat, 16 Jan 2010 00:00:00 +0100 3284383 http://www.medworm.com/index.php?rid=3284382&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20156149%26dopt%3DAbstract Authors: Yaccato K, Carhart R, Hagemeyer A, Herrmann M, Lesik A, Strasser P, Volpe A, Turner H, Weinberg H State-of-art water gas shift catalysts (FeCr for high temperature shift and CuZn for low temperature shift) are not active enough to be used in fuel processors for the production of hydrogen from hydrocarbon fuels for fuel cells. The need for drastically lower catalyst volumes has triggered a search for novel WGS catalysts that are an order of magnitude more active than current systems. Novel catalytic materials for the high, medium and low temperature water gas shift reactions have been discovered by application of combinatorial methodologies. Catalyst libraries were synthesized on 4 inch wafers in 16x16 arrays and screened in a high throughput scanning mass spectrometer in the t... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3284382 Sat, 16 Jan 2010 00:00:00 +0100 3284382 http://www.medworm.com/index.php?rid=3104615&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20015013%26dopt%3DAbstract Authors: Rungrotmongkol T, Udommaneethanakit T, Frecer V, Miertus S Using computer-assisted combinatorial chemistry techniques, we have designed a virtual library of anti-influenza agents, analogs of inhibitor A-315675, containing a novel pyrrolidine core, which effectively inhibits both wild type and common oseltamivir-resistant mutant forms of the neuraminidase (NA) subtype N1 of avian influenza virus H5N1. A target-specific Potential of Mean Force (PMF) scoring function parameterized on a training set of 13 known pyrrolidine-based inhibitors of NA and validated on 3 others was used to predict the N1 inhibition constants for the focused library of A-315675 analogs. Nine virtual hits (best pyrrolidine inhibitors designed in the present study) are predicted to exhibit inhibition consta... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3104615 Wed, 16 Dec 2009 00:00:00 +0100 3104615 http://www.medworm.com/index.php?rid=3104614&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20015014%26dopt%3DAbstract Authors: Moss ML, Rasmussen FH, Nudelman R, Dempsey PJ, Williams J Fluorescence resonance energy transfer substrates were designed and tested as substrates for ADAM9. The donor/quencher pair used were 5-carboxy fluorescein (Fam) and 4-(4-dimethyl-aminophenylazo)benzoyl (Dabcyl) since they have been well studied sensitive fluorescent probes. The peptides based on precursor TNF-alpha, Dabcyl-Ser-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Lys(Fam)- NH2 and Dabcyl-Leu-Ala-Gln-Ala-HomoPhe-Arg-Ser-Lys(Fam)- NH2, and C-terminal TGF-alpha, Dabcyl-Glu-His-Ala-Asp-Leu-Leu-Ala-Val-Val-Ala-Ala-Lys(Fam)- NH2 cleavage sites were effectively processed by ADAM9 with turnover numbers of 100 +/- 20 x 10-2 min-1, 20 +/- 10 x 10-2 min-1, and 10 +/- 3 x 10-2 min-1. In addition, a peptide based on the 33kDa cleava... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3104614 Wed, 16 Dec 2009 00:00:00 +0100 3104614 http://www.medworm.com/index.php?rid=3104613&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20015015%26dopt%3DAbstract Authors: Hoflack L, De Groeve M, Desmet T, Van Gerwen P, Soetaert W A calorimetric assay is described for the high-throughput screening of enzymes that produce inorganic phosphate. In the current example, cellobiose phosphorylase (EC 2.4.1.20) is tested for its ability to synthesise rare disaccharides. The generated phosphate is measured in a high-throughput calorimeter by coupling the reaction to pyruvate oxidase and catalase. This procedure allows for the simultaneous analysis of 48 reactions in microtiter plate format and has been validated by comparison with a colorimetric phosphate assay. The proposed assay has a coefficient of variation of 3.14% and is useful for screening enzyme libraries for enhanced activity and substrate libraries for enzyme promiscuity. PMID: 20015015 [P... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3104613 Wed, 16 Dec 2009 00:00:00 +0100 3104613 http://www.medworm.com/index.php?rid=3104612&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20015016%26dopt%3DAbstract Authors: Erickson HS, Gannot G, Tangrea MA, Chuaqui RF, Gillespie JW, Emmert-Buck MR The capacity to rapidly and efficiently elucidate a reliable set of disease specific biomarkers is paramount to enable a future of personalized medicine. High throughput screening methods applied to human clinical samples for the discovery of diagnostic, prognostic, and therapeutic targets address this need. Although the ability to analyze either thousands of markers from one sample or one marker from thousands of samples is the current state of high throughput screening, it would be ideal to have the ability to analyze thousands of markers from thousands of samples to expedite the early discovery phase of biomarkers and their validation. This review summarizes the current state of high throughput scre... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3104612 Wed, 16 Dec 2009 00:00:00 +0100 3104612 http://www.medworm.com/index.php?rid=3104611&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20015017%26dopt%3DAbstract Authors: Chang B, Levin J, Thompson WA, Fairbrother WG High-throughput immunoprecipitation (IP) studies of transcription factors and splicing factors have revolutionized the fields of transcription and splicing. Recent location studies on Nova1/2 and Fox2 have identified a set of cellular targets of these splicing factors. One problem with identifying binding sites for splicing factors arises from the transient role of RNA in gene expression. The primary role of most splicing factors is to bind pre-mRNA co-transcriptionally and participate in the extremely rapid process of splice site selection and catalysis. Pre-mRNA is a labile species with a steady state level that is three orders of magnitude (10-3) less abundant than mRNA. As many splicing factors also bind mRNA to some degree, th... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3104611 Wed, 16 Dec 2009 00:00:00 +0100 3104611 http://www.medworm.com/index.php?rid=3104610&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20015018%26dopt%3DAbstract In this study, we investigated the miniaturisation of a HTS kinase assay and compared the real life performance of current state-of-the-art air displacement transfer technology (MiniTrak V System) and a capillary based nanolitre dispenser (CyBi-HummingWell). The robustness and effectiveness of the miniaturised assay formats were compared by testing staurosporine to generate dose-response curves and 340 previously identified active compounds. Using the MiniTrak device, assay miniaturisation was achieved from 18 microL to 6 microL in 384-well and 1536-well plate formats. Utilising the nanolitre dispenser, miniaturisation was performed down to 5 microL in 1536-well plates. The Z' factors obtained for each assay format were consistently above 0.5. The data presented here describe the reproduci... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3104610 Wed, 16 Dec 2009 00:00:00 +0100 3104610 http://www.medworm.com/index.php?rid=3104609&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20015019%26dopt%3DAbstract Authors: Kahn M, Seubsai A, Onal I, Senkan S Nanoparticles of 35 individual metals as well as their binary combinations were synthesized using high-throughput pulsed laser ablation (PLA), and collected on Al2O3, CeO2, SiO2, TiO2, and ZrO2 pellets. These materials were then screened for their catalytic activities and selectivities for the partial oxidation of propylene, in particular for propylene oxide (PO), using array channel microreactors. Reaction conditions were the following: 1 atm pressure, gas hourly space velocity (GHSV) of 20,000 h-1, temperature 300 degrees C, 333 degrees C, and 367 degrees C, and feed gas composition 20 vol% O2, 20 vol% C3H6 and balance He. Initial screening experiments resulted in the discovery of SiO2 supported Cr, Mn, Cu, Ru, Pd, Ag, Sn, and Ir as the mo... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3104609 Wed, 16 Dec 2009 00:00:00 +0100 3104609 http://www.medworm.com/index.php?rid=3104608&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20015020%26dopt%3DAbstract Authors: Pegan SD, Tian Y, Sershon V, Mesecar AD The malachite green assay is often used for measuring the presence of inorganic mono-phosphate concentrations. Some studies have adapted this assay for use in monitoring enzymatic reactions and have suggested its potential use in high throughput screening (HTS). With the increasing availability of laboratory automation, some studies are starting to explore the possibility of conducting limited, semi-automated versions of the assay. Here we report the optimization and complete adaptation of the malachite green assay to a fully automated, HTS platform that can be performed unattended with standard, commercially available, automated liquid-handling systems. The assay is universal for the majority of enzymes that release phosphate or pyropho... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3104608 Wed, 16 Dec 2009 00:00:00 +0100 3104608 http://www.medworm.com/index.php?rid=3104607&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20015021%26dopt%3DAbstract Authors: Mozrzymas A, Różycka-Roszak B A quantitative structure - property relationship (QSPR) was used to predict the critical micelle concentration (cmc) of nonionic surfactants. The relation was developed for a diverse set of 23 nonionic surfactants (r = 0.99, F-test = 1042.5) employing the connectivity and valence connectivity indices only. The molecular connectivity indices were calculated for the whole molecule which was a simple and general approach. PMID: 20015021 [PubMed - as supplied by publisher] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=3104607 Wed, 16 Dec 2009 00:00:00 +0100 3104607 http://www.medworm.com/index.php?rid=2121310&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19149491%26dopt%3DAbstract Authors: Korsgaard MP, Strøbæk D, Christophersen P Planar chip technology has strongly facilitated the progress towards fully automated electrophysiological systems that, in contrast to the traditional patch clamp technology, have the capability of parallel compound testing. The throughput has been increased from testing below 10 compounds per day to a realized capacity approaching high throughput levels. Many pharmaceutical companies have implemented automated planar chip electrophysiology in their drug discovery process, particularly at the levels of lead optimization, secondary screening and safety testing, whereas primary screening is generally not performed. In this review, we briefly discuss the technology and give examples from selected NeuroSearch ion channel programs... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2121310 Thu, 22 Jan 2009 08:00:21 +0100 2121310 http://www.medworm.com/index.php?rid=2121314&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19149487%26dopt%3DAbstract Authors: Krafte DS PMID: 19149487 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2121314 Thu, 01 Jan 2009 05:00:00 +0100 2121314 http://www.medworm.com/index.php?rid=2121313&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19149488%26dopt%3DAbstract Authors: Jegla TJ, Zmasek CM, Batalov S, Nayak SK Ion channels are intimately involved in virtually every physiological process of consequence in humans. Their importance is underscored by the identification of numerous "channelopathies", human diseases caused by ion channel mutations. Ion Channels have consequently been viewed as fertile ground for drug discovery and, indeed, they represent one of the largest target classes for current medicines. The future prospects of ion channels as a target class are tied to the functional characterization of the human ion channel set on a genomic scale. The focus of this review is to describe the molecular diversity and conservation of human ion channels. The human genome contains at least 232 genes that encode the pore-forming subunits of plasma... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2121313 Thu, 01 Jan 2009 05:00:00 +0100 2121313 http://www.medworm.com/index.php?rid=2121312&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19149489%26dopt%3DAbstract Authors: Farre C, Haythornthwaite A, Haarmann C, Stoelzle S, Kreir M, George M, Brüggemann A, Fertig N Ion channel dysfunction is known to underlie several acute and chronic disorders and, therefore, ion channels have gained increased interest as drug targets. During the past decade, ion channel screening platforms have surfaced that enable high throughput drug screening from a more functional perspective. These two factors taken together have further inspired the development of more refined screening platforms, such as the automated patch clamp platforms described in this article. Approximately six years ago, Nanion introduced its entry level device for automated patch clamping - the Port-a-Patch. With this device, Nanion offers the world's smallest patch-clamp workstation, whils... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2121312 Thu, 01 Jan 2009 05:00:00 +0100 2121312 http://www.medworm.com/index.php?rid=2121311&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19149490%26dopt%3DAbstract We describe here the main features and potential applications of OpusXpress, an efficient commercially available system for automated recording from Xenopus oocytes. We show some types of data that have been gathered by this system and review realized and potential applications. PMID: 19149490 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2121311 Thu, 01 Jan 2009 05:00:00 +0100 2121311 http://www.medworm.com/index.php?rid=2121309&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19149492%26dopt%3DAbstract Authors: Maher MP, Wu NT, Guo HQ, Dubin AE, Chaplan SR, Wickenden AD Hyperpolarization- and Cyclic Nucleotide-gated (HCN) channels are a family of six transmembrane domain, single pore-loop, hyperpolarization activated, non-selective cation channels. The HCN family consists of four members (HCN1-4). HCN channels represent the molecular correlates of I(h) (also known as 'funny' I(f) and 'queer' I(q)), a hyperpolarization-activated current best known for its role in controlling heart rate and in the regulation of neuronal resting membrane potential and excitability. A significant body of molecular and pharmacological evidence is now emerging to support a role for these channels in the function of sensory neurons and pain sensation, particularly pain associated with nerve or tissue injury... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2121309 Thu, 01 Jan 2009 05:00:00 +0100 2121309 http://www.medworm.com/index.php?rid=2121308&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19149493%26dopt%3DAbstract Authors: Lepple-Wienhues A, Lassen D, Hümmer A, Czubayko U, Knirsch M, Golubovic A To facilitate automated patch clamp measurements of ion channels in cells, the development of an all-glass Chiptip pipette is reported that may be combined with the previously described Flip-the-Tip technology. A single measurement requires less than 50 cells, and the addition of drugs for screening can be limited to very low volumes down to 1 microL. This apparatus is suitable for the study small cells, subcellular organelles and bacteria. PMID: 19149493 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2121308 Thu, 01 Jan 2009 05:00:00 +0100 2121308 http://www.medworm.com/index.php?rid=2121307&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19149494%26dopt%3DAbstract We present detailed analyses of the QPatch features and results in case studies in which secondary screening assays were successfully developed for a voltage-gated calcium channel and a ligand-gated TRP channel. The increase in throughput compared to conventional patch clamp with the same cells was approximately 10-fold. We conclude that the QPatch, combining high data quality and speed with user friendliness and suitability for a wide array of ion channels, resides on the cutting edge of automated patch clamp technology and plays a pivotal role in expediting ion channel drug discovery. PMID: 19149494 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2121307 Thu, 01 Jan 2009 05:00:00 +0100 2121307 http://www.medworm.com/index.php?rid=2121306&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19149495%26dopt%3DAbstract This article focuses on several complex and difficult to express ion channels and illustrates how improved stable cell lines can be obtained by integration of planar array electrophysiology systems into the cell line generation process per se. By embedding this approach at multiple stages (e.g., during development of the expression strategy, during screening and validation of clonal lines, and during characterisation of the final cell line), the cycle time and success rate in obtaining robust expression of complex multi-subunit channels can be significantly improved. We also review how recent advances in this technology (e.g., population patch clamp) have further widened the versatility and applicability of this approach. PMID: 19149495 [PubMed - in process] (Source: Combinatorial Chem... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2121306 Thu, 01 Jan 2009 05:00:00 +0100 2121306 http://www.medworm.com/index.php?rid=2121305&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19149496%26dopt%3DAbstract Authors: Castle N, Printzenhoff D, Zellmer S, Antonio B, Wickenden A, Silvia C Voltage dependent sodium channels are widely recognized as valuable targets for the development of therapeutic interventions for neuroexcitatory disorders such as epilepsy and pain as well as cardiac arrhythmias. An ongoing challenge for sodium channel drug discovery is the ability to readily evaluate state dependent interactions, which are known to underlie inhibition by many clinically used local anesthetic, antiepileptic and antiarrhythmic sodium channel blockers. While patch-clamp electrophysiology is still considered the most effective way of measuring ion channel function and pharmacology, it does not have the throughput to be useful in early stages of drug discovery in which there is often a need to e... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2121305 Thu, 01 Jan 2009 05:00:00 +0100 2121305 http://www.medworm.com/index.php?rid=2046291&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19075599%26dopt%3DAbstract Authors: Voigt K, Brüggemann R Pharmaceuticals are omnipresent in waste-water world-wide. Research has shown that many pharmaceuticals are not completely removed during wastewater treatment, and as a result, this has led to their occurrence being reported in waste water treatment plant effluents, rivers and lakes, and more rarely in groundwater and in drinking water. Hence, it is only logical that pharmaceutical residues in the environment and their potential toxic effects have been recognized as one of the emerging research areas in environmental chemistry. A lack of data, especially ecotoxicological and fate data on pharmaceuticals, is evident. The extent to which data are missing should therefore be looked upon in more detail in order to trigger further political steps in perfo... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2046291 Mon, 01 Dec 2008 05:00:00 +0100 2046291 http://www.medworm.com/index.php?rid=2046290&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19075600%26dopt%3DAbstract Authors: Duchowicz PR, Castr EA There exists a great amount of information on ranking methods provided in the literature, a new appealing methodology that is generally dealt in a so mathematical fashion. Ranking strategies are applied in a wide range of scientific fields, such as Decision Support, Toxicology, Environmental Research, Analytical Chemistry, Food Chemistry, QSPR-QSAR, etc. When contrasted to other multi-criteria data analyzes, Partial Order Ranking results in a very transparent and suitable way to perform comparisons among a set of objects (such as molecules) according to their attributes (molecular descriptors) values. The scope of this review is to explore such sorting ideas and to provide the non-specialist reader with insights into this formalism applied to QSPR-QSAR s... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2046290 Mon, 01 Dec 2008 05:00:00 +0100 2046290 http://www.medworm.com/index.php?rid=2046289&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19075601%26dopt%3DAbstract Authors: Carlsen L This review summarizes the use of partial order ranking (POR) techniques for the assessment of chemicals. Simple partial order ranking may advantageously be applied to give the single chemicals investigated an identity in relation to other substances. Thus, it constitutes an effective tool for the prioritization of chemicals, e.g., based on their PBT (Persistence, Bioaccumulating, Toxicity) characteristics. In more elaborate cases where a larger number of descriptors are taken into account, e.g., comprising physico-chemical characteristics, atmospheric parameters, geospecific factors, and possibly socio-economic factors, hierarchical partial order ranking (HPOR) may be applied. Thus, in a first ordering step, a series of meta-descriptors are generated that later subs... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2046289 Mon, 01 Dec 2008 05:00:00 +0100 2046289 http://www.medworm.com/index.php?rid=2046288&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19075602%26dopt%3DAbstract Authors: Zumárraga M, Vaz Domínguez C, Camarero S, Shleev S, Polaina J, Martínez-Arias A, Ferrer M, De Lacey AL, Fernández VM, Ballesteros A, Plou FJ, Alcalde M A mutant laccase from the Ascomycete Myceliophthora thermophila has been submitted to iterative cycles of combinatorial saturation mutagenesis through in vivo overlap extension in Saccharomyces cerevisiae. Over 180,000 clones were explored, among which the S510G mutant revealed a direct interaction between the conserved (509)VSG(511) tripeptide, located in the neighborhood of the T1 site, and the C-terminal plug. The K(m)(O)(2) value of the mutant increased 1.5-fold, and the electron transfer pathway between the reducing substrate and the T1 copper ion was altered, improving the catalytic efficiency towards ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2046288 Mon, 01 Dec 2008 05:00:00 +0100 2046288 http://www.medworm.com/index.php?rid=2046287&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19075603%26dopt%3DAbstract Authors: Urban DJ, Zheng W, Goker-Alpan O, Jadhav A, Lamarca ME, Inglese J, Sidransky E, Austin CP Glucocerebrosidase (GC) catalyzes the hydrolysis of beta-glucocerebroside to glucose and ceramide in lysosomes. Mutations in the glucocerebrosidase gene (GBA) result in Gaucher disease, an autosomal recessive lysosomal storage disorder. Many of the mutations encountered in patients with Gaucher disease are missense alterations that may cause misfolding, decreased stability and/or mistrafficking of this lysosomal protein. Some inhibitors of GC have been shown to act as chemical chaperones, stabilizing the conformation of mutant proteins and thus restoring their function. High throughput screening (HTS) of small molecule libraries for such compounds with potential for chaperone therapy requ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2046287 Mon, 01 Dec 2008 05:00:00 +0100 2046287 http://www.medworm.com/index.php?rid=2046286&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19075604%26dopt%3DAbstract Authors: Andreae MR, Steiner T, Hueber M, Schopfer U, Smith R, Igo D, Cantrell D, Hohos A, Kiwanuka A The demand for organized storage concepts to maintain, collect and distribute compounds has grown not only at pharmaceutical companies, but also at smaller research organizations and academic laboratories where there is the demand to store and retrieve substances systematically. However, budget limitations have prevented these smaller groups from buying costly storage systems offered by specialized commercial vendors. On the other hand, within pharmaceutical companies a need for inexpensive and flexible storage concepts has developed and complements the existing automated archives. For reasons of efficiency, most companies have built centralized facilities holding large collections of ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2046286 Mon, 01 Dec 2008 05:00:00 +0100 2046286 http://www.medworm.com/index.php?rid=2046285&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19075605%26dopt%3DAbstract Authors: Tsai CC, Chen CJ, Tseng HW, Hua KF, Tsai RY, Lai MH, Chao LK, Chen ST Procedures for cytomic screening were developed for identifying compounds with immuno-modulating properties from the crude extracts of natural products. Human peripheral blood mononuclear cells (hPB-MNCs) were first cultured with different natural crude extracts for 12 hours in culture media. By analyzing the expression of early activation CD69 marker, the potential immuno-activating properties of ethanol extracts of Calocedrus formosana were observed. By the double staining of antibodies recognizing CD69 and specific cell type markers, the increase of CD69 expressions was observed in CD3 and CD14 cell populations. To examine the immuno-activating properties in CD3 T cells and CD14 monocytes, the extracts we... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2046285 Mon, 01 Dec 2008 05:00:00 +0100 2046285 http://www.medworm.com/index.php?rid=2046284&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19075606%26dopt%3DAbstract This study evidenced the effectiveness and versatility of this new member of the supported guanidine superbases as an attractive candidate to replace the bases usually employed in organic synthesis during the implementation of environmentally friendly preparative processes. PMID: 19075606 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=2046284 Mon, 01 Dec 2008 05:00:00 +0100 2046284 http://www.medworm.com/index.php?rid=1951425&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18991572%26dopt%3DAbstract Authors: Brüggemann R PMID: 18991572 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1951425 Sat, 01 Nov 2008 04:00:00 +0100 1951425 http://www.medworm.com/index.php?rid=1951424&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18991573%26dopt%3DAbstract Authors: Hefferlin R The periodic law, manifested in the chart of the elements, is so fundamental in chemistry and related areas of physics that the question arises "Might periodicity among molecules also be embodied in a periodic system?" This review paper details how a particular periodic system of gas-phase diatomic molecules, allowing for the forecasting of thousands of new data, was developed. It can include ionized and even quarked-nuclei molecules and it coincides with locality (averaging) and the additivity found in some data; it has interesting vector properties, and it may be related in challenging ways to partial order. The review then explains how periodic systems for triatomic and four-atomic species are evolving along a similar path. The systems rest largely upon exhausti... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1951424 Sat, 01 Nov 2008 04:00:00 +0100 1951424 http://www.medworm.com/index.php?rid=1951423&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18991574%26dopt%3DAbstract Authors: El-Basil S Combinatorial properties of graphs and groups of physico-chemical interest are described. A type of mathematical modeling is applied which involves "translating" algebraic expressions into graphs. The idea is applied to both graph theory and group theory. The former topic includes objects of importance in physics and chemistry such as trees, polyomino graphs, king boards, etc. Our study along these lines emphasizes nonadjacency relations, graph-generation, quasicrystals, continued fractions, fractals, and general ordering schemes of graphs. The second part of the paper considers certain colored graphs as models of several group-theoretical concepts including coset representations of groups, subduction of groups, character tables, and mark tables which are essential ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1951423 Sat, 01 Nov 2008 04:00:00 +0100 1951423 http://www.medworm.com/index.php?rid=1951422&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18991575%26dopt%3DAbstract Authors: Klein DJ, Ivanciuc T, Ryzhov A, Ivanciuc O Reaction networks are viewed as derived from ordinary molecular structures related in reactant-product pairs so as to manifest a chemical super-structure. Such super-structures then are candidates for applications in a general combinatoric chemistry. Notable additional characterization of a reaction super-structure occurs when such reaction graphs are directed, as for example when there is progressive substitution (or addition) on a fixed molecular skeleton. Such a set of partially ordered entities is in mathematics termed a poset, which further manifests a number of special properties, as then might be utilized in different applications. Focus on the overall "super-structural" poset goes beyond ordinary molecular structure in attendi... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1951422 Sat, 01 Nov 2008 04:00:00 +0100 1951422 http://www.medworm.com/index.php?rid=1951421&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18991576%26dopt%3DAbstract Authors: De Loof K, De Baets B, De Meyer H, Brüggemann R When ranking objects (like chemicals, geographical sites, river sections, etc.) by multicriteria analysis, it is in most cases controversial and difficult to find a common scale among the criteria of concern. Therefore, ideally, one should not resort to such artificial additional constraints. The theory of partially ordered sets (or posets for short) provides a solid formal framework for the ranking of objects without assigning a common scale and/or weights to the criteria, and therefore constitutes a valuable alternative to traditional approaches. In this paper, we aim to give a comprehensive literature review on the topic. First we formalize the problem of ranking objects according to some predefined criteria. In this theo... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1951421 Sat, 01 Nov 2008 04:00:00 +0100 1951421 http://www.medworm.com/index.php?rid=1951420&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18991577%26dopt%3DAbstract Authors: Rademaker M, De Baets B, De Meyer H We discuss various ways in which to construct and process partial order relations or partially ordered sets (posets) in the context of ranking objects on the basis of multiple criteria. Oftentimes, it is undesirable or even impossible to devise a weighting scheme to compute a final score on the basis of the criteria. An alternative is then to restrict oneself to the information contained in the partial ordering of all objects implied by the criteria. We will consider some ways in which one can exploit partial order relations to determine a ranking of a collection of objects. More exactly, we will examine how to combine information coming from two sources, both for the case in which the sources are considered to be equally important, as well ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1951420 Sat, 01 Nov 2008 04:00:00 +0100 1951420 http://www.medworm.com/index.php?rid=1951419&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18991578%26dopt%3DAbstract Authors: Brüggemann R, Voigt K Principles of partial order applied to ranking are explained. The Hasse diagram technique (HDT) is the application of partial order theory based on a data matrix. In this paper, HDT is introduced in a stepwise procedure, and some elementary theorems are exemplified. The focus is to show how the multivariate character of a data matrix is realized by HDT and in which cases one should apply other mathematical or statistical methods. Many simple examples illustrate the basic theoretical ideas. Finally, it is shown that HDT is a useful alternative for the evaluation of antifouling agents, which was originally performed by amoeba diagrams. PMID: 18991578 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1951419 Sat, 01 Nov 2008 04:00:00 +0100 1951419 http://www.medworm.com/index.php?rid=1806106&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18795876%26dopt%3DAbstract Authors: Maréchal E PMID: 18795876 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1806106 Mon, 01 Sep 2008 04:00:00 +0100 1806106 http://www.medworm.com/index.php?rid=1806105&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18795877%26dopt%3DAbstract Authors: Maréchal E Chemogenomics is the study of the interaction of functional biological systems with exogenous small molecules, or in broader sense the study of the intersection of biological and chemical spaces. Chemogenomics requires expertises in biology, chemistry and computational sciences (bioinformatics, cheminformatics, large scale statistics and machine learning methods) but it is more than the simple apposition of each of these disciplines. Biological entities interacting with small molecules can be isolated proteins or more elaborate systems, from single cells to complete organisms. The biological space is therefore analyzed at various postgenomic levels (genomic, transcriptomic, proteomic or any phenotypic level). The space of small molecules is partially real, corr... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1806105 Mon, 01 Sep 2008 04:00:00 +0100 1806105 http://www.medworm.com/index.php?rid=1806104&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18795878%26dopt%3DAbstract Authors: Peuchmaur M, Wong YS Diversity-Oriented Synthesis (DOS) aims to broaden the frontier of accessible collections of complex and diverse small molecules. This review endeavours to dissect the DOS concept through three elements of diversity: building block, stereochemistry, and skeleton. Recent examples in the literature that emphasize the efficient combinations of these elements to generate diversity are reported. PMID: 18795878 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1806104 Mon, 01 Sep 2008 04:00:00 +0100 1806104 http://www.medworm.com/index.php?rid=1806103&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18795879%26dopt%3DAbstract Authors: Wolff M, Kredel S, Wiedenmann J, Nienhaus GU, Heilker R The more recently discovered anthozoan fluorescent proteins (FPs) and the classic Aequorea victoria Green Fluorescent Protein (avGFP) as well as their derivatives have become versatile tools as live cell markers in fluorescence microscopy. In this review, we show the use of these FPs in drug discovery assays. Assay examples are given for the application of FPs in multiplexed imaging, as photosensitizers, as fluorescent timers, as pulse-chase labels and for robotically integrated compound testing. The development of fast microscopic imaging devices has enabled the application of automated fluorescence microscopy combined with image analysis to pharmaceutical high throughput drug discovery assays, generally referred to as H... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1806103 Mon, 01 Sep 2008 04:00:00 +0100 1806103 http://www.medworm.com/index.php?rid=1806102&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18795880%26dopt%3DAbstract We describe how cell-based screening assays can be designed to maximize the likelihood of discovering selective compounds through the choice of positive readouts, low chemical concentrations and long incubation periods. Examining the potency, efficacy and activity range of chemicals can further help set apart those likely to act more specifically. Identifying the cellular targets of active chemicals can be especially demanding. Secondary screens and the cautious use of the candidate approach can help narrow down their mechanisms of action, but biased approaches may lead to the identification of secondary or even irrelevant targets. We discuss strategies for unbiased target identification by sampling potential targets at the genome-wide and proteome-wide levels. PMID: 18795880 [PubMed -... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1806102 Mon, 01 Sep 2008 04:00:00 +0100 1806102 http://www.medworm.com/index.php?rid=1806101&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18795881%26dopt%3DAbstract Authors: Lafanechère L Microtubules are still a promising target for new therapeutic agents. Thus, there is a continuous interest for compounds able to modify microtubule assembly, either by interacting directly with tubulin, or by interacting with microtubules regulators. Because of its dynamic characteristics, the microtubule cytoskeleton is a suitable target for small molecules that rapidly diffuse in the cell cytoplasm. Moreover, compounds targeting the microtubule cytoskeleton have proved to be valuable tools for basic research in cell biology. In this paper, after a short presentation of the apparent molecular pathways involved in the anticancer effect of agents that interfere with microtubules functions, the potentials and impact of chemogenomics and cell-based assays in th... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1806101 Mon, 01 Sep 2008 04:00:00 +0100 1806101 http://www.medworm.com/index.php?rid=1806100&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18795882%26dopt%3DAbstract Authors: Muskavitch MA, Barteneva N, Gubbels MJ Infectious diseases caused by protozoan parasites - malaria, sleeping sickness, leishmaniasis, Chagas' disease, toxoplasmosis - remain chronic problems for humanity. We lack vaccines and have limited drug options effective against protozoa. Research into anti-protozoan drugs has accelerated with improved in vitro cultivation methods, enhanced genetic accessibility, completed genome sequences for key protozoa, and increased prominence of protozoan diseases on the agendas of well-resourced public figures and foundations. Concurrent advances in high-throughput screening (HTS) technologies and availability of diverse small molecule libraries offer the promise of accelerated discovery of new drug targets and new drugs that will reduce disease ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1806100 Mon, 01 Sep 2008 04:00:00 +0100 1806100 http://www.medworm.com/index.php?rid=1806099&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18795883%26dopt%3DAbstract Authors: Miyashita M, Miyagawa H As plants lack a circulatory system and adaptive immune system, they have evolved their own defense systems distinct from animals, in which each plant cell is capable of defending itself from pathogens. Plants induce a number of defense responses, which are triggered by a variety of molecules derived from pathogenic microorganisms, referred to as microbe-associated molecular patterns (MAMPs), including peptides, proteins, lipopolysaccharide, beta-glucan, chitin, and ergosterol. The interaction between plants and chemicals in the context of plant defense represents a "natural" and simple model for chemogenomics, at the intersection between chemical and biological diversities. For protection of crop plants from diseases, it has been shown to be effective ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1806099 Mon, 01 Sep 2008 04:00:00 +0100 1806099 http://www.medworm.com/index.php?rid=1806098&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18795884%26dopt%3DAbstract Authors: Kersey P, Lonsdale D, Mulder NJ, Petryszak R, Apweiler R Assignment of function to protein sequence is a task of growing importance in the life sciences, as new high-throughput sequencing DNA technologies generate ever increasing quantities of genomic and meta-genomic data. Patterns within the sequence space, caused by the evolutionary conservation and assembly of protein domains, make possible the inference of function from sequence similarity. Clustering similar sequences is a useful technique for finding conserved sequences; the CluSTr database is a publicly-available database arranging proteins in a hierarchy structured by similarity. The protein classification tool InterProScan builds on this approach by applying a range of methods to detect proteins that contain signatur... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1806098 Mon, 01 Sep 2008 04:00:00 +0100 1806098 http://www.medworm.com/index.php?rid=1806097&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18795885%26dopt%3DAbstract This article reviews the application of fragment descriptors at different stages of virtual screening: filtering, similarity search, and direct activity assessment using QSAR/QSPR models. Several case studies are considered. It is demonstrated that the power of fragment descriptors stems from their universality, very high computational efficiency, simplicity of interpretation and versatility. PMID: 18795885 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1806097 Mon, 01 Sep 2008 04:00:00 +0100 1806097 http://www.medworm.com/index.php?rid=1806096&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18795886%26dopt%3DAbstract Authors: Gregori-Puigjané E, Mestres J The practical implementation and validation of a ligand-based approach to mining the chemogenomic space of drugs is presented and applied to the in silico target profiling of 767 drugs against 684 targets of therapeutic relevance. The results reveal that drugs targeting aminergic G protein-coupled receptors (GPCRs) show the most promiscuous pharmacological profiles. The detection of cross-pharmacologies between aminergic GPCRs and the opioid, sigma, NMDA, and 5-HT3 receptors aggravate the potential promiscuity of those drugs, predominantly including analgesics, antidepressants, and antipsychotics. PMID: 18795886 [PubMed - as supplied by publisher] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1806096 Mon, 01 Sep 2008 04:00:00 +0100 1806096 http://www.medworm.com/index.php?rid=1806095&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18795887%26dopt%3DAbstract Authors: Vert JP, Jacob L Support vector machines and kernel methods belong to the same class of machine learning algorithms that has recently become prominent in both computational biology and chemistry, although both elds have largely ignored each other. These methods are based on a sound mathematical and computationally efficient framework that implicitly embeds the data of interest, respectively proteins and small molecules, in high-dimensional feature spaces where various classification or regression tasks can be performed with linear algorithms. In this review, we present the main ideas underlying these approaches, survey how both the "biological" and the "chemical" spaces have been separately constructed using the same mathematical framework and tricks, and suggest different ave... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1806095 Mon, 01 Sep 2008 04:00:00 +0100 1806095 http://www.medworm.com/index.php?rid=1704593&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18694385%26dopt%3DAbstract Authors: Zaman GJ PMID: 18694385 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1704593 Fri, 01 Aug 2008 04:00:00 +0100 1704593 http://www.medworm.com/index.php?rid=1704592&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18694386%26dopt%3DAbstract Authors: Wunder F, Kalthof B, Müller T, Hüser J Functional cell-based assays have gained increasing importance for microplate-based high throughput screening (HTS). The use of high-density microplates, most prominently 1536-well plates, and miniaturized assay formats allow screening of comprehensive compound collections with more than 1 million compounds at ultra-high throughput, i.e. in excess of 100,000 samples per day. uHTS operations with numerous campaigns per year should generally support this throughput at all different steps of the process, including the underlying compound logistics, the (automated) testing of the corporate compound collection in the bioassay, and the subsequent follow-up studies for hit confirmation and characterization. A growing number of reports ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1704592 Fri, 01 Aug 2008 04:00:00 +0100 1704592 http://www.medworm.com/index.php?rid=1704591&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18694387%26dopt%3DAbstract Authors: Hanson GT, Hanson BJ A fluorescent probe is a fluorophore designed to localize within a specific region of a biological specimen or to respond to a specific stimulus. Fluorescent probes have been used for nearly a century to study cellular processes due to their exquisite sensitivity and selectivity. Fluorescent probes have also gained in popularity as safety and environmental concerns over the use of radioactive probes have grown. At the same time, cellular assays are being more widely used now than ever before. This review will give a broad overview of types of fluorescent probes, types of fluorescent assays, and their application in cellular assays for a number of pharmaceutically relevant target classes. PMID: 18694387 [PubMed - in process] (Source: Combinatorial Chemi... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1704591 Fri, 01 Aug 2008 04:00:00 +0100 1704591 http://www.medworm.com/index.php?rid=1704590&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18694388%26dopt%3DAbstract Authors: Dunlop J, Bowlby M, Peri R, Tawa G, Larocque J, Soloveva V, Morin J Ion channels are attractive targets for drug discovery with recent estimates indicating that voltage and ligand-gated channels account for the third and fourth largest gene families represented in company portfolios after the G protein coupled and nuclear hormone receptor families. A historical limitation on ion channel targeted drug discovery in the form of the extremely low throughput nature of the gold standard assay for assessing functional activity, patch clamp electrophysiology in mammalian cells, has been overcome by the implementation of multi-well plate format cell-based screening strategies for ion channels. These have taken advantage of various approaches to monitor ion flux or membrane potential us... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1704590 Fri, 01 Aug 2008 04:00:00 +0100 1704590 http://www.medworm.com/index.php?rid=1704589&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18694389%26dopt%3DAbstract Authors: Gasparri F, Sola F, Bandiera T, Moll J, Galvani A High-content analysis (HCA) is a term used to describe techniques involving multiplexed analysis of fluorescent markers to measure multiple cellular responses to biological stimuli or drug treatment. HCA is usually based on automated microscopy or related technologies, and its value lies in providing multiparametric information on single cells within a population. During the last decade, several HCA approaches have been developed and applied to assess cellular mechanism of action of pharmacologically relevant compounds identified through biochemical screening or similar in vitro methods. With automation and instrument development, these approaches have evolved to the extent that the technique is now routinely used in screening ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1704589 Fri, 01 Aug 2008 04:00:00 +0100 1704589 http://www.medworm.com/index.php?rid=1704588&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18694390%26dopt%3DAbstract Authors: Henriksen U, Fog J, Loechel F, Præstegaard M Multiplexing of GFP based and immunofluorescence translocation assays enables easy acquisition of multiple readouts from the same cell in a single assay run. Immunofluorescence assays monitor translocation, phosphorylation, and up/down regulation of endogenous proteins. GFP-based assays monitor translocation of stably expressed GFP-fusion proteins. Such assays may be multiplexed along (vertical), across (horizontal), and between (branch) signal pathways. Examples of these strategies are presented: 1) The MK2-GFP assay monitors translocation of MK2-GFP from the nucleus to the cytoplasm in response to stimulation of the p38 pathway. By applying different immunofluorescent assays to the MK2 assay, a multiplexed HCA system is creat... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1704588 Fri, 01 Aug 2008 04:00:00 +0100 1704588 http://www.medworm.com/index.php?rid=1704587&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18694391%26dopt%3DAbstract Authors: Zhu PJ, Zheng W, Auld DS, Jadhav A, Macarthur R, Olson KR, Peng K, Dotimas H, Austin CP, Inglese J Nuclear translocation is an important step in glucocorticoid receptor (GR) signaling and assays that measure this process allow the identification of nuclear receptor ligands independent of subsequent functional effects. To facilitate the identification of GR-translocation agonists, an enzyme fragment complementation (EFC) cell-based assay was scaled to a 1536-well plate format to evaluate 9,920 compounds using a quantitative high throughput screening (qHTS) strategy where compounds are assayed at multiple concentrations. In contrast to conventional assays of nuclear translocation the qHTS assay described here was enabled on a standard luminescence microplate reader precluding th... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1704587 Fri, 01 Aug 2008 04:00:00 +0100 1704587 http://www.medworm.com/index.php?rid=1704586&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18694392%26dopt%3DAbstract Authors: Eglen RM, Gilchrist A, Reisine T For most membrane-bound molecular targets, including G protein linked receptors (GPCRs), the optimal approach in drug discovery involves the use of cell based high throughput screening (HTS) technologies to identify compounds that modulate target activity. Most GPCRs have been cloned and can therefore be routinely expressed in immortalized cell lines. These cells can be easily and rapidly grown in unlimited quantities making them ideal for use in current HTS technologies. A significant advantage of this approach is that immortalized recombinant cells provide a homogenous background for expression of the target which greatly facilitates consistency in screening, thus allowing for a better understanding of the mechanism of action of the interacti... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1704586 Fri, 01 Aug 2008 04:00:00 +0100 1704586 http://www.medworm.com/index.php?rid=1704585&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18694393%26dopt%3DAbstract Authors: Eglen RM, Gilchrist A, Reisine T Cellular technologies are widely used in drug discovery to treat human diseases. Most studies involve the expression of recombinant targets in immortalized cells and measure drug interactions using simple, quantifiable responses. Such cells are also amenable to high throughput screening (HTS) methods. However, the cell phenotype employed in HTS is often determined by the assay technology available, rather than the physiological relevance of the cell background. They are, therefore, suboptimal surrogates for cells that accurately reflect human diseases. Consequently, there is growing interest in adopting primary and embryonic stem cells in drug discovery. Primary cells are already used in secondary screening assays in conjunction with confocal i... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1704585 Fri, 01 Aug 2008 04:00:00 +0100 1704585 http://www.medworm.com/index.php?rid=1704584&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18694394%26dopt%3DAbstract This article will describe these technologies and their applications in measuring cell proliferation, cell attachment and spreading, cell apoptosis and their application for several receptor target classes, including receptor tyrosine kinases and G protein-coupled receptors. The potential utility and drawbacks of these tools for high throughput screening, directed screening and compound profiling will also be discussed. PMID: 18694394 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1704584 Fri, 01 Aug 2008 04:00:00 +0100 1704584 http://www.medworm.com/index.php?rid=1686043&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18673269%26dopt%3DAbstract Authors: Houston D, Costanzi S, Jacobson KA, Harden TK The P2Y(1) receptor is a member of the P2Y family of nucleotide-activated G protein-coupled receptors, and it is an important therapeutic target based on its broad tissue distribution and essential role in platelet aggregation. We have designed a set of highly selective and diverse pharmacological tools for studying the P2Y(1) receptor using a rational approach to ligand design. Based on the discovery that bisphosphate analogues of the P2Y(1) receptor agonist, ADP, are partial agonists/competitive antagonists of this receptor, an iterative approach was used to develop competitive antagonists with enhanced affinity and selectivity. Halogen substitutions of the 2-position of the adenine ring provided increased affinity while an N(6) ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1686043 Tue, 01 Jul 2008 04:00:00 +0100 1686043 http://www.medworm.com/index.php?rid=1682657&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18673268%26dopt%3DAbstract Authors: Willard FS, Siderovski DP PMID: 18673268 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1682657 Tue, 01 Jul 2008 04:00:00 +0100 1682657 http://www.medworm.com/index.php?rid=1682656&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18673269%26dopt%3DAbstract Authors: Houston D, Costanzi S, Jacobson KA, Harden TK The P2Y(1) receptor is a member of the P2Y family of nucleotide-activated G protein-coupled receptors, and it is an important therapeutic target based on its broad tissue distribution and essential role in platelet aggregation. We have designed a set of highly selective and diverse pharmacological tools for studying the P2Y(1) receptor using a rational approach to ligand design. Based on the discovery that bisphosphate analogues of the P2Y(1) receptor agonist, ADP, are partial agonists/competitive antagonists of this receptor, an iterative approach was used to develop competitive antagonists with enhanced affinity and selectivity. Halogen substitutions of the 2-position of the adenine ring provided increased affinity while an N(6) ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1682656 Tue, 01 Jul 2008 04:00:00 +0100 1682656 http://www.medworm.com/index.php?rid=1682655&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18673270%26dopt%3DAbstract Authors: Jensen NH, Roth BL The National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (PDSP) is a resource that provides free screening of novel compounds to academic investigators. This program differs from other public-sector screening programs in that compounds are screened against a large panel of transmembrane receptors, channels, and transporters, a selection that currently includes a large portion of the whole neuro-receptorome. This review discusses the research areas that can profit from this resource, exemplified by recent findings. The first area is the identification of side effects of medications. Examples include the identification of the histamine H(1) receptor as being responsible for weight gain under antipsychotic treatment and the association... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1682655 Tue, 01 Jul 2008 04:00:00 +0100 1682655 http://www.medworm.com/index.php?rid=1682654&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18673271%26dopt%3DAbstract Authors: Whitehurst CE, Annis DA Advances in combinatorial chemistry and genomics have inspired the development of novel affinity selection-based screening techniques that rely on mass spectrometry to identify compounds that preferentially bind to a protein target. Of the many affinity selection-mass spectrometry techniques so far documented, only a few solution-based implementations that separate target-ligand complexes away from unbound ligands persist today as routine high throughput screening platforms. Because affinity selection-mass spectrometry techniques do not rely on radioactive or fluorescent reporters or enzyme activities, they can complement traditional biochemical and cell-based screening assays and enable scientists to screen targets that may not be easily amenable to ot... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1682654 Tue, 01 Jul 2008 04:00:00 +0100 1682654 http://www.medworm.com/index.php?rid=1682653&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18673272%26dopt%3DAbstract Authors: Chiu ML, Tsang C, Grihalde N, Macwilliams MP With the advent of the recent determination of high-resolution crystal structures of bovine rhodopsin and human beta2 adrenergic receptor (beta2AR), there are still many structure-function relationships to be learned from other G protein-coupled receptors (GPCRs). Many of the pharmaceutically interesting GPCRs cannot be modeled because of their amino acid sequence divergence from bovine rhodopsin and beta2AR. Structure determination of GPCRs can provide new avenues for engineering drugs with greater potency and higher specificity. Several obstacles need to be overcome before membrane protein structural biology becomes routine: over-expression, solubilization, and purification of milligram quantities of active and stable GPCRs. Coord... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1682653 Tue, 01 Jul 2008 04:00:00 +0100 1682653 http://www.medworm.com/index.php?rid=1682652&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18673273%26dopt%3DAbstract Authors: Gupta A, Heimann AS, Gomes I, Devi LA Antibodies are components of the body's humoral immune system that are generated in response to foreign pathogens. Modern biomedical research has employed these very specific and efficient molecules designed by nature in the diagnosis of diseases, localization of gene products as well as in the rapid screening of targets for drug discovery and testing. In addition, the introduction of antibodies with fluorescent or enzymatic tags has significantly contributed to advances in imaging and microarray technology, which are revolutionizing disease research and the search for effective therapeutics. More recently antibodies have been used in the isolation of dimeric G protein-coupled receptor (GPCR) complexes. In this review, we discuss antibodie... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1682652 Tue, 01 Jul 2008 04:00:00 +0100 1682652 http://www.medworm.com/index.php?rid=1682651&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18673274%26dopt%3DAbstract In this study the relationship between in vitro single time point high throughput microsomal stability and in vivo clearance from abbreviated drug discovery pharmacokinetics studies was examined using 306 real world drug discovery compounds. The results showed that in vitro Phase I microsomal stability t(1/2) is significantly correlated to in vivo clearance with a p-value < 0.001. For compounds with low in vitro rat microsomal stability (t(1/2) < 15 min), 87% showed high clearance in vivo (CL > 25 mL/min/kg). This demonstrates that high throughput microsomal stability data are very effective in identifying compounds with significant clearance liabilities in vivo. For compounds with high in vitro rat microsomal stability (t(1/2) > 15 min), no significant differentiation was obse... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1682651 Tue, 01 Jul 2008 04:00:00 +0100 1682651 http://www.medworm.com/index.php?rid=1682650&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18673275%26dopt%3DAbstract Authors: Li C, Wang J, Zhan Y, Wang J Based on the classification of 20 amino acids, we reduce a protein primary sequence to six (0,1) sequences. For each of them, two so-called normalized relative-entropies are calculated and thus a 12-D vector is constructed to describe the protein primary sequence. The examination of similarities/dissimilarities among eight different proteins illustrates the utility of the approach. PMID: 18673275 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1682650 Tue, 01 Jul 2008 04:00:00 +0100 1682650 http://www.medworm.com/index.php?rid=1682649&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18673276%26dopt%3DAbstract Authors: Lipkin MJ, Stevens AP, Livingstone DJ, Harris CJ Increasingly, chemical libraries are being produced which are focused on a biological target or group of related targets, rather than simply being constructed in a combinatorial fashion. A screening collection compiled from such libraries will contain multiple analogues of a number of discrete series of compounds. The question arises as to how many analogues are necessary to represent each series in order to ensure that an active series will be identified. Based on a simple probabilistic argument and supported by in-house screening data, guidelines are given for the number of compounds necessary to achieve a "hit", or series of hits, at various levels of certainty. Obtaining more than one hit from the same series is useful since... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1682649 Tue, 01 Jul 2008 04:00:00 +0100 1682649 http://www.medworm.com/index.php?rid=1507810&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18537554%26dopt%3DAbstract Authors: Willard FS, Siderovski DP PMID: 18537554 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1507810 Sun, 01 Jun 2008 04:00:00 +0100 1507810 http://www.medworm.com/index.php?rid=1507809&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18537555%26dopt%3DAbstract Authors: Kenakin T In high throughput screening systems, a single concentration of a new compound is tested in a biological system to detect direct effects (agonists) or effects on other ligands (antagonists). In this latter case, the chemical context of the assay is defined by a balance of maximal sensitivity (limited agonist concentration) and maximal window to observe effect (sizable agonist concentration to induce measurable effect). For allosteric modulators, there are other factors that should be considered in high throughput screening environments. Specifically, the saturable aspect of allosteric effect can dissociate the observed ordinate change in response (% inhibition) and potency of effect (concentration at which a given ordinate % effect is obtained). Also, the specter of ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1507809 Sun, 01 Jun 2008 04:00:00 +0100 1507809 http://www.medworm.com/index.php?rid=1507808&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18537556%26dopt%3DAbstract This article presents recent advances and associated applications for screening of GPCRs and other receptor species through the rapid measurement of protein phosphorylation events, such as ERK phosphorylation, as new readouts for drug discovery. PMID: 18537556 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1507808 Sun, 01 Jun 2008 04:00:00 +0100 1507808 http://www.medworm.com/index.php?rid=1507807&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18537557%26dopt%3DAbstract This article reviews the principles and potential of current label-free cell assay technologies in GPCR drug discovery. PMID: 18537557 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1507807 Sun, 01 Jun 2008 04:00:00 +0100 1507807 http://www.medworm.com/index.php?rid=1507806&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18537558%26dopt%3DAbstract Authors: Johnston CA, Willard FS, Ramer JK, Blaesius R, Roques CN, Siderovsk DP Heterotrimeric G-proteins, comprising Galpha, Gbeta, and Ggamma subunits, are molecular switches that regulate numerous signaling pathways involved in cellular physiology. This characteristic is achieved by the adoption of two principal states: an inactive state in which GDP-bound Galpha is complexed with the Gbetagamma dimer, and an active state in which GTP-bound Galpha is freed of its Gbetagamma binding partner. Structural studies have illustrated the basis for the distinct conformations of these states which are regulated by alterations in three precise 'switch regions' of the Galpha subunit. Discrete differences in conformation between GDP- and GTP-bound Galpha underlie its nucleotide-dependent protein... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1507806 Sun, 01 Jun 2008 04:00:00 +0100 1507806 http://www.medworm.com/index.php?rid=1507805&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18537559%26dopt%3DAbstract Authors: Smrcka AV, Lehmann DM, Dessal AL G proteins mediate the action of G protein coupled receptors (GPCRs), a major target of current pharmaceuticals and a major target of interest in future drug development. Most pharmaceutical interest has been in the development of selective GPCR agonists and antagonists that activate or inhibit specific GPCRs. Some recent thinking has focused on the idea that some pathologies are the result of the actions of an array of GPCRs suggesting that targeting single receptors may have limited efficacy. Thus, targeting pathways common to multiple GPCRs that control critical pathways involved in disease has potential therapeutic relevance. G protein betagamma subunits released from some GPCRs upon receptor activation regulate a variety of downstream path... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1507805 Sun, 01 Jun 2008 04:00:00 +0100 1507805 http://www.medworm.com/index.php?rid=1507804&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18537560%26dopt%3DAbstract Authors: Kimple AJ, Yasgar A, Hughes M, Jadhav A, Willard FS, Muller RE, Austin CP, Inglese J, Ibeanu GC, Siderovski DP, Simeonov A The GoLoco motif is a short Galpha-binding polypeptide sequence. It is often found in proteins that regulate cell-surface receptor signaling, such as RGS12, as well as in proteins that regulate mitotic spindle orientation and force generation during cell division, such as GPSM2/LGN. Here, we describe a high throughput fluorescence polarization (FP) assay using fluorophore-labeled GoLoco motif peptides for identifying inhibitors of the GoLoco motif interaction with the G-protein alpha subunit Galpha (i1). The assay exhibits considerable stability over time and is tolerant to DMSO up to 5%. The Z'-factors for robustness of the GPSM2 and RGS12 GoLoco motif as... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1507804 Sun, 01 Jun 2008 04:00:00 +0100 1507804 http://www.medworm.com/index.php?rid=1481698&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18473737%26dopt%3DAbstract This study shows how chemistry knowledge and reasoning are taken into account for building a new methodology that aims at automatically grouping data having a chronological structure. We consider combinatorial catalytic experiments where the evolution of a reaction (e.g., conversion) over time is expected to be analyzed. The mathematical tool has been developed to compare and group curves taking into account their shape. The strategy, which consists on combining a hierarchical clustering with the k-means algorithm, is described and compared with both algorithms used separately. The hybridization is shown to be of great interest. Then, a second application mode of the proposed methodology is presented. Once meaningful clusters according to chemist's preferences and goals are successfully ac... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481698 Thu, 01 May 2008 04:00:00 +0100 1481698 http://www.medworm.com/index.php?rid=1481697&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18473738%26dopt%3DAbstract Authors: Overk CR, Yao P, Chen S, Deng S, Imai A, Main M, Schinkovitz A, Farnsworth NR, Pauli GF, Bolton JL Symptoms associated with menopause can greatly affect the quality of life for women. Botanical dietary supplements have been viewed by the public as safe and effective despite a lack of evidence indicating a urgent necessity to standardize these supplements chemically and biologically. Seventeen plants were evaluated for estrogenic biological activity using standard assays: competitive estrogen receptor (ER) binding assay for both alpha and beta subtypes, transient transfection of the estrogen response element luciferase plasmid into MCF-7 cells expressing either ER alpha or ER beta, and the Ishikawa alkaline phosphatase induction assay for both estrogenic and antiestrogenic acti... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481697 Thu, 01 May 2008 04:00:00 +0100 1481697 http://www.medworm.com/index.php?rid=1481696&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18473739%26dopt%3DAbstract Authors: Charton J, Charruault L, Deprez-Poulain R, Deprez B Many natural privileged scaffolds contain a basic nitrogen atom, which often is a key element of pharmacophore and a chemically reactive centre as well. In our ongoing research program devoted to the design of targeted libraries based on acidic templates, we developed methods to convert privileged basic compounds -like natural alkaloids or drugs into acidic compounds. This conversion led to a profound alteration of the pharmacophore, without changing the overall shape and lipophilicity of the molecule. We expect such modifications to generate unexpected biological activities. Recently, we focused on derivatives of squaric acid, a vinylogous carboxylic acid. Two series were studied. First we describe a new, selective parallel ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481696 Thu, 01 May 2008 04:00:00 +0100 1481696 http://www.medworm.com/index.php?rid=1481695&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18473740%26dopt%3DAbstract Authors: Hansen KB, Bräuner-Osborne H, Egebjerg J Generation of in vitro cellular assays using fluorescence measurements at heterologously expressed NMDA receptors would speed up the process of ligand characterization and enable high-throughput screening. The major drawback to the development of such assays is the cytotoxicity caused by Ca(2+)-flux into the cell via NMDA receptors upon prolonged activation by agonists present in the culture medium. In the present study, we established four cell lines with stable expression of NMDA receptor subtypes NR1/NR2A, NR1/NR2B, NR1/NR2C, or NR1/NR2D in BHK-21 cells. To assess the usefulness of the stable cell lines in conjunction with intracellular calcium ([Ca(2+)](i)) measurements for evaluation of NMDA receptor pharmacology, several liga... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481695 Thu, 01 May 2008 04:00:00 +0100 1481695 http://www.medworm.com/index.php?rid=1481694&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18473741%26dopt%3DAbstract Authors: Kim HJ, Yun HM, Kim T, Nam G, Roh EJ, Kostenis E, Choo HY, Pae AN, Rhim H Continuous identification and validation of novel drug targets require the development of rapid, reliable, and sensitive cell-based high-throughput screening (HTS) methods for proposed targets. Recently, the 5-HT(6) receptor (5-HT(6)R), a member of the class of recently discovered 5-HT receptors, has received considerable attention for its possible implications in depression, cognition, and anxiety. However, the cellular signaling mechanisms of 5-HT(6)R are poorly understood due to the lack of selective 5-HT(6)R ligands. In the present study, we examined functional coupling of the human 5-HT(6)R, 5-HT(7A)R, or 5-HT(7B)R with various Galpha-proteins (Galpha (15), Galpha (qs5), or Galpha (qG66Ds5)) to deve... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481694 Thu, 01 May 2008 04:00:00 +0100 1481694 http://www.medworm.com/index.php?rid=1481693&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18473742%26dopt%3DAbstract Authors: Taipa MA In the demanding field of proteomics, there is an urgent need for affinity-catcher molecules to implement effective and high throughput methods for analysing the human proteome or parts of it. Antibodies have an essential role in this endeavour, and selection, isolation and characterisation of specific antibodies represent a key issue to meet success. Alternatively, it is expected that new, well-characterised affinity reagents generated in rapid and cost-effective manners will also be used to facilitate the deciphering of the function, location and interactions of the high number of encoded protein products. Combinatorial approaches combined with high throughput screening (HTS) technologies have become essential for the generation and identification of robust affinity... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481693 Thu, 01 May 2008 04:00:00 +0100 1481693 http://www.medworm.com/index.php?rid=1481707&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336210%26dopt%3DAbstract Authors: Wesche H, Xiao SH, Young S PMID: 18336210 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481707 Sat, 01 Mar 2008 05:00:00 +0100 1481707 http://www.medworm.com/index.php?rid=1481706&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336211%26dopt%3DAbstract Authors: Kassner PD High throughput technologies have the potential to affect all aspects of drug discovery. Considerable attention is paid to high throughput screening (HTS) for small molecule lead compounds. The identification of the targets that enter those HTS campaigns had been driven by basic research until the advent of genomics level data acquisition such as sequencing and gene expression microarrays. Large-scale profiling approaches (e.g., microarrays, protein analysis by mass spectrometry, and metabolite profiling) can yield vast quantities of data and important information. However, these approaches usually require painstaking in silico analysis and low-throughput basic wet-lab research to identify the function of a gene and validate the gene product as a potential therapeut... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481706 Sat, 01 Mar 2008 05:00:00 +0100 1481706 http://www.medworm.com/index.php?rid=1481705&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336212%26dopt%3DAbstract Authors: Lü Q, An WF Ion channels are a large superfamily of membrane proteins that pass ions across membranes. They are critical to diverse physiological functions in both excitable and nonexcitable cells and underlie many diseases. As a result, they are an important target class which is proven to be highly "druggable". However, for high throughput screening (HTS), ion channels are historically difficult as a target class due to their unique molecular properties and the limitations of assay technologies that are HTS-amendable. In this article, we describe the background of ion channels and current status and challenges for ion channel drug discovery, followed by an overview of both conventional and newly emerged ion channel screening technologies. The critical impact of such new... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481705 Sat, 01 Mar 2008 05:00:00 +0100 1481705 http://www.medworm.com/index.php?rid=1481704&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336213%26dopt%3DAbstract Authors: Xiao SH, Reagan JD, Lee PH, Fu A, Schwandner R, Zhao X, Knop J, Beckmann H, Young SW GPCRs had significant representation in the drug discovery portfolios of most major commercial drug discovery organizations for many years. This is due in part to the diverse biological roles mediated by GPCRs as a class, as well as the empirical discovery that they have proven relatively tractable to the development of small molecule therapeutics. Publication of the human genome sequence in 2001 confirmed GPCRs as the largest single gene superfamily with more than 700 members, furthering the already strong appeal of addressing this target class using efficient and highly parallelized platform approaches. The GPCR research platform implemented at Amgen is used as a case study to review the evo... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481704 Sat, 01 Mar 2008 05:00:00 +0100 1481704 http://www.medworm.com/index.php?rid=1481703&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336214%26dopt%3DAbstract Authors: Denner P, Schmalowsky J, Prechtl S High-Content Analysis (HCA) has developed into an established tool and is used in a wide range of academic laboratories and pharmaceutical research groups. HCA is now routinely proving to be effective in providing functionally relevant results. It is essential to select the appropriate HCA application with regard to the targeted compound's cellular function. The cellular impact and compound specificity as revealed by HCA analysis facilitates reaching definitive conclusions at an early stage in the drug discovery process. This technology therefore has the potential to substantially improve the efficiency of pharmaceutical research. Recent advances in fluorescent probes have significantly boosted the success of HCA. Auto-fluorescent proteins wh... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481703 Sat, 01 Mar 2008 05:00:00 +0100 1481703 http://www.medworm.com/index.php?rid=1481702&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336215%26dopt%3DAbstract Authors: Shiau AK, Massari ME, Ozbal CC Small molecule high-throughput screening in drug discovery today is dominated by techniques which are dependent upon artificial labels or reporter systems. While effective, these approaches can be affected by certain experimental limitations, such as conformational restrictions imposed by the selected label or compound fluorescence/quenching. Label-free approaches potentially address many of these issues by allowing researchers to investigate more native systems without fluorescence- or luminescence-based readouts. However, due to throughput and expense constraints, label-free methods have been largely relegated to a supporting role as the basis of secondary assays. In this review, we describe recent improvements in impedance-based, optical biose... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481702 Sat, 01 Mar 2008 05:00:00 +0100 1481702 http://www.medworm.com/index.php?rid=1481701&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336216%26dopt%3DAbstract We describe the recent development of high throughput and high-content screens (HCS) for neurodegenerative diseases, with a focus on inherited neurodegenerative disorders, such as Huntington's disease. We describe, among others, HTS assays based on protein aggregation, neuronal death, caspase activation and mutant protein clearance. Furthermore, we describe high-content screens that are being used to prioritize hits identified in such HTS assays. These assays and screening approaches should accelerate drug discovery for neurodegenerative disorders and guide the development of screening approaches for other complex disease phenotypes. PMID: 18336216 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481701 Sat, 01 Mar 2008 05:00:00 +0100 1481701 http://www.medworm.com/index.php?rid=1481700&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336217%26dopt%3DAbstract Authors: Ling XB High throughput screening (HTS), an industrial effort to leverage developments in the areas of modern robotics, data analysis and control software, liquid handling devices, and sensitive detectors, has played a pivotal role in the drug discovery process, allowing researchers to efficiently screen millions of compounds to identify tractable small molecule modulators of a given biological process or disease state and advance them into high quality leads. As HTS throughput has significantly increased the volume, complexity, and information content of datasets, lead discovery research demands a clear corporate strategy for scientific computing and subsequent establishment of robust enterprise-wide (usually global) informatics platforms, which enable complicated HTS work fl... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481700 Sat, 01 Mar 2008 05:00:00 +0100 1481700 http://www.medworm.com/index.php?rid=1481699&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336218%26dopt%3DAbstract Authors: Carlson TJ, Fisher MB With the increase in the numbers of molecules synthesized in a typical drug discovery program, as well as the large amount of information utilized in the selection of a drug candidate, there is a need for a plethora of drug metabolism and pharmacokinetic (DMPK) information to be regularly generated in discovery. Over the past decade, many in vitro, and even in vivo, DMPK screens have been developed and routinely deployed to generate this information in support of drug discovery efforts. In the past few years, newer methods, or adaptations to methods, have been published, and this review attempts to summarize these advances. In particular, advances have been reported for experimental approaches to metabolic clearance, CYP inhibition, in vivo exposure, and ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481699 Sat, 01 Mar 2008 05:00:00 +0100 1481699 http://www.medworm.com/index.php?rid=1481716&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336201%26dopt%3DAbstract Cominatorial chemistry & high throughput screening. Editorial from Guest Editors. Comb Chem High Throughput Screen. 2008 Feb;11(2):84-5 Authors: Büning H, Buchholz CJ PMID: 18336201 [PubMed - indexed for MEDLINE] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481716 Fri, 01 Feb 2008 05:00:00 +0100 1481716 http://www.medworm.com/index.php?rid=1481715&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336202%26dopt%3DAbstract Authors: Mäkelä AR, Oker-Blom C High throughput screening is a core technology in drug discovery. During the past decade, several strategies have been developed to screen (poly)peptide libraries for diverse applications including disease diagnosis and profiling, imaging, as well as therapy. The recently established baculovirus display vector system (BDVS) represents a eukaryotic screening platform that combines the positive attributes of both cell and virus-based display approaches, allowing presentation of complex polypeptides on cellular and viral surfaces. Compared to microbial display systems, the BDVS has the advantage of correct protein folding and post-translational modifications similar to those in mammals, facilitating expression and analysis of proteins with therape... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481715 Fri, 01 Feb 2008 05:00:00 +0100 1481715 http://www.medworm.com/index.php?rid=1481714&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336203%26dopt%3DAbstract Authors: Buchholz CJ, Duerner LJ, Funke S, Schneider IC Retroviruses distinguish themselves from all other mammalian viruses by their abilities to infect and propagate in mammalian cells without causing a cytopathic effect and to stably integrate their genetic information into the genome of the host cell. These unique properties make them an ideal platform for the display and directed evolution of proteins in a mammalian cell environment. This review will describe the essentials about retrovirus biology and then discuss in detail display and screening strategies that have been developed during the past 15 years of retroviral display technology. PMID: 18336203 [PubMed - indexed for MEDLINE] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481714 Fri, 01 Feb 2008 05:00:00 +0100 1481714 http://www.medworm.com/index.php?rid=1481713&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336204%26dopt%3DAbstract Authors: Lim KI, Schaffer DV Retroviral and lentiviral based gene delivery vectors have been used in numerous pre-clinical studies and clinical trials due to their advantages, including stable and prolonged expression of therapeutic transgenes and minimal immune responses against the vector. Despite such advantages, however, retroviral vectors also have several limitations for gene therapy applications. For example, they can suffer from a lack of efficient or targeted gene delivery to key cell types. In addition, retroviral vector stability can be compromised by their envelope proteins. This review briefly describes how such limitations have been overcome by recently developed library selection approaches that borrow a lesson from nature: the ability of evolution to generate biomolecul... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481713 Fri, 01 Feb 2008 05:00:00 +0100 1481713 http://www.medworm.com/index.php?rid=1481712&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336205%26dopt%3DAbstract Authors: Perabo L, Huber A, Märsch S, Hallek M, Büning H After attracting the attention of the scientific community due to a number of favourable characteristics that make it an attractive vector for human gene therapy [1,2], AAV has been thoroughly investigated in the past two decades. Standard technologies for the manipulation of the viral genome and for efficient packaging and purification protocols have paved the road for trial and error manipulation by educated guesses to study viral infectious biology by reverse genetics and to generate improved vectors for human gene transfer. However, despite remarkable progress, our limited knowledge of molecular mechanisms implicated in virus-cell interactions has been a limiting factor. Combinatorial engineering and high-throughput... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481712 Fri, 01 Feb 2008 05:00:00 +0100 1481712 http://www.medworm.com/index.php?rid=1481711&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336206%26dopt%3DAbstract Authors: Pepper LR, Cho YK, Boder ET, Shusta EV Yeast surface display has become an increasingly popular tool for protein engineering and library screening applications. Recent advances have greatly expanded the capability of yeast surface display, and are highlighted by cell-based selections, epitope mapping, cDNA library screening, and cell adhesion engineering. In this review, we discuss the state-of-the-art yeast display methodologies and the rapidly expanding set of applications afforded by this technology. PMID: 18336206 [PubMed - indexed for MEDLINE] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481711 Fri, 01 Feb 2008 05:00:00 +0100 1481711 http://www.medworm.com/index.php?rid=1481710&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336207%26dopt%3DAbstract Authors: Borghouts C, Kunz C, Groner B Peptide aptamers are molecules that bind to protein targets and are able to interfere with their functions. In the past, important achievements have been made using such peptide aptamers in different approaches and for various purposes. Peptide aptamers are comprised of a variable peptide region of 8 to 20 amino acids in length, which is displayed by a scaffold protein. An overview of the numerous scaffold proteins that have been investigated for their suitability to present peptide aptamers will be given. To identify peptide aptamers efficiently and specifically binding to a predetermined target, two eukaryotic systems have been used in multiple studies: a modified version of the Gal4 yeast-two-hybrid system and the optimized LexA interaction tra... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481710 Fri, 01 Feb 2008 05:00:00 +0100 1481710 http://www.medworm.com/index.php?rid=1481709&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336208%26dopt%3DAbstract Authors: Blancafort P, Beltran AS Artificial Transcription Factors (ATFs) are engineered DNA-binding proteins designed to bind specific sequences of DNA. ATFs made of Zinc Finger (ZF) domains have been developed to regulate specific genes and phenotypes both in cells and whole organisms. Recently, an emerging application of engineered DNA-binding domains include the specific editing of the genome, the ability to specifically cut, recombine, modify DNA and image protein-nucleic acid interactions in living cells. In this review we will summarize the techniques used for the rational design, screening and functional selection of ZF proteins in mammalian cell systems and their applications in areas of biotechnology, functional genomics and molecular therapeutics. The in vivo specificity of ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481709 Fri, 01 Feb 2008 05:00:00 +0100 1481709 http://www.medworm.com/index.php?rid=1481708&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18336209%26dopt%3DAbstract Authors: Stürzl M, Konrad A, Sander G, Wies E, Neipel F, Naschberger E, Reipschläger S, Gonin-Laurent N, Horch RE, Kneser U, Hohenberger W, Erfle H, Thurau M Reversely transfected cell microarrays (RTCM) have been introduced as a method for parallel high throughput analysis of gene functions in mammalian cells. Hundreds to thousands of different recombinant DNA or RNA molecules can be transfected into different cell clusters at the same time on a single glass slide with this method. This allows either the simultaneous overexpression or--by using the recently developed RNA interference (RNAi) techniques--knockdown of a huge number of target genes. A growing number of sophisticated detection systems have been established to determine quantitatively the effects of the transfecte... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481708 Fri, 01 Feb 2008 05:00:00 +0100 1481708 http://www.medworm.com/index.php?rid=1481729&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18220538%26dopt%3DAbstract Authors: Choi Y, van Breemen RB A high throughput screening assay for the identification of ligands to pharmacologically significant receptors was developed based on magnetic particles containing immobilized receptors followed by liquid chromatography-mass spectrometry (LC-MS). This assay is suitable for the screening of complex mixtures such as botanical extracts. For proof-of-principle, estrogen receptor-alpha (ER-alpha) and ER-beta were immobilized on magnetic particles functionalized with aldehyde or carboxylic acid groups. Alternatively, biotinylated ER was immobilized onto streptavidin-derivatized magnetic particles. The ER that was immobilized using the streptavidin-biotin chemistry showed higher activity than that immobilized on aldehyde or carboxylic acid functionalized magnet... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481729 Tue, 01 Jan 2008 05:00:00 +0100 1481729 http://www.medworm.com/index.php?rid=1481728&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18220539%26dopt%3DAbstract Authors: Konkimalla VB, Efferth T The cure rates in cancer chemotherapy are affected by the development of drug resistance and severe side effects. Due to these limitations, there is an urgent need for improved therapeutics. Bioactive compounds from medicinal plants represent a valuable resource for novel anticancer drugs. To gain a systematic approach, we established a library of 531 cytotoxic natural products derived from traditional Chinese medicine. Cellular and pharmacogenomic profiling was performed for the 10 most cytotoxic natural products. One of these compounds, helebrin, was analyzed in more detail. The IC(50) values for hellebrin of 60 NCI cell lines were associated with the microarray-based expression of 9,706 genes. By hierarchical cluster analyses, candidate genes were i... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481728 Tue, 01 Jan 2008 05:00:00 +0100 1481728 http://www.medworm.com/index.php?rid=1481727&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18220540%26dopt%3DAbstract Authors: Adler A, Forster N, Homann M, Göringer HU African trypanosomes are the causative agent of sleeping sickness. The therapeutics used to control and treat the disease are very ineffective and thus, the development of improved drugs is urgently needed. Recently, new strategies for the design of novel trypanocidals have been put forward. Among them are techniques that rely on parasite-specific RNA aptamers. One approach involves the aptamer-directed transport of lytic compounds to the lysosome of the parasite. The aptamer has been termed 2-16 RNA and here we report the optimization of the RNA for its applications in vivo. To convert aptamer 2-16 into a serum-stable reagent 2'-deoxy-2'-F- and/or 2'-deoxy-2'-NH(2)-uridine- and cytidine-substituted RNAs were generated. While 2'-N... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481727 Tue, 01 Jan 2008 05:00:00 +0100 1481727 http://www.medworm.com/index.php?rid=1481726&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18220541%26dopt%3DAbstract Authors: Kozlov IA, Melnyk PC, Hachmann JP, Srinivasan A, Shults M, Zhao C, Musmacker J, Nelson N, Barker DL, Lebl M We have developed a miniaturized and multiplexed solution assay for the measurement of protease activity in complex samples. This technology can accelerate research in functional proteomics and enable biologists to carry out multiplexed protease inhibitor screens on a large scale. The assay readout is based on Illumina's universal Sentrix BeadArrays. The peptide sequences that serve as protease substrates are conjugated to oligonucleotide sequences complementary to the oligo tags on randomly assembled and decoded bead arrays. The peptide portion is C-terminally labeled with a biotin residue and contains a sequence of five histidine residues on the amino terminus. The uni... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481726 Tue, 01 Jan 2008 05:00:00 +0100 1481726 http://www.medworm.com/index.php?rid=1481725&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18220542%26dopt%3DAbstract Authors: Lesch B, Thomson DW, Lindell SD The primary literature concerning the combinatorial synthesis of organophosphorus compounds is reviewed and discussed. The subject matter is divided into three main sections describing the solid phase, solution phase and solvent-free synthesis of phosphorus containing organic molecules. The review covers the synthesis of compounds in which the final products contain phosphorus-carbon bonds, primarily phosphonates, phosphinates, phosphine oxides and phosphines. PMID: 18220542 [PubMed - indexed for MEDLINE] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481725 Tue, 01 Jan 2008 05:00:00 +0100 1481725 http://www.medworm.com/index.php?rid=1481724&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18220543%26dopt%3DAbstract Authors: Paz K, Hadari YR Recently, significant progress has been made towards understanding the pathogenesis of cancer from the molecular standpoint. To this end, a growing number of approaches are being exploited for the identification and validation of new therapeutic targets suitable for potent and specific intervention. The type 1 insulin-like growth factor receptor (IGF-1R) system has recently become the focus of major attention in the arena of cancer research. The involvement of the receptor and its downstream signaling cascades in the carcinogenesis process makes this system an excellent target for potential cancer therapy. Indeed, advances in the understanding of the molecular mechanisms behind IGF-1R activation have led to the discovery of agents designed selectively for targ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481724 Tue, 01 Jan 2008 05:00:00 +0100 1481724 http://www.medworm.com/index.php?rid=1481723&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18220544%26dopt%3DAbstract Authors: Sachinidis A, Sotiriadou I, Seelig B, Berkessel A, Hescheler J Cell replacement therapy of severe degenerative diseases such as diabetes, myocardial infarction and Parkinson's disease through transplantation of somatic cells generated from embryonic stem (ES) cells is currently receiving considerable attention for the therapeutic applications. ES cells harvested from the inner cell mass (ICM) of the early embryo, can proliferate indefinitely in vitro while retaining the ability to differentiate into all somatic cells thereby providing an unlimited renewable source of somatic cells. In this context, identifying soluble factors, in particular chemically synthesized small molecules, and signal cascades involved in specific differentiation processes toward a defined tissue specifi... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481723 Tue, 01 Jan 2008 05:00:00 +0100 1481723 http://www.medworm.com/index.php?rid=1481722&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18288946%26dopt%3DAbstract Authors: Baxendale IR, Hayward JJ, Ley SV Microwave chemistry has already impacted significantly on the everyday synthesis of organic molecules. The adoption and integration of this liberating technology has permitted a resurrection of many synthetic transformations that were previously considered too extreme in their conditions (temperatures, pressures, reaction times) to be synthetically useful. Furthermore, whole arrays of additional chemical transformations have been devised under microwave heating that allow access to more diverse chemical architectures via more expedient routes. Continuous flow processing of chemical intermediates taking advantage of the unique heating mechanism and characteristics of microwave irradiation will certainly be the next evolutionary step forward in t... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481722 Sat, 01 Dec 2007 05:00:00 +0100 1481722 http://www.medworm.com/index.php?rid=1481721&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18288947%26dopt%3DAbstract Authors: Dai WM, Shi J Diversity-oriented organic synthesis (DOS) and solid-phase organic synthesis (SPOS) are proven technologies for generating small molecule libraries for chemical genetics studies. Integration of controlled microwave heating with DOS and SPOS not only speeds up the library preparation process but also offers unique opportunities in tackling issues which are hardly addressed by thermal heating. Microwave-assisted synthesis is illustrated for (a) highly regioselective Wittig olefination of cycloalkanones by accurate regulation of temperature; (b) tandem Wittig-IMDA sequence toward stereochemical diversity of gamma-butyrolactones; (c) one-pot alkylation-amidation approach toward appendage diversity through use of building blocks; and (d) one-pot U-4CR-annulation strat... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481721 Sat, 01 Dec 2007 05:00:00 +0100 1481721 http://www.medworm.com/index.php?rid=1481720&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18288948%26dopt%3DAbstract Authors: O'Neill JC, Blackwell HE Diketopiperazines (DKPs) are a well-known class of heterocycles that have recently emerged as a promising biologically active scaffold. Solid-phase organic synthesis has become an important tool in the combinatorial exploration of these privileged structures, expediting the synthesis and, therefore, the discovery of active compounds. To date, certain DKPs have shown potent activities against a range of diseases and biological phenomena, including bacterial infections, various cancers, asthma, infertility, premature labor, and HIV. Recent applications of solid-phase DKP synthesis, with a particular focus on cyclative cleavage and microwave-assisted reactions, are highlighted herein. PMID: 18288948 [PubMed - indexed for MEDLINE] (Source: Combinatoria... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481720 Sat, 01 Dec 2007 05:00:00 +0100 1481720 http://www.medworm.com/index.php?rid=1481719&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18288949%26dopt%3DAbstract Authors: de la Hoz A, Díaz-Ortiz A, Moreno A, Sanchéz-Migallón A, Prieto P, Carrillo JR, Vázquez E, Gómez MV, Herrero MA Microwave irradiation has been successfully applied in organic chemistry. Spectacular accelerations, higher yields under milder reaction conditions and higher product purities have all been reported. Indeed, a number of authors have described success in reactions that do not occur under conventional heating and modifications in selectivity (chemo-, regio- and stereoselectivity) have even been reported. Recent advances in microwave-assisted combinatorial chemistry include high-speed solid-phase and polymer-supported organic synthesis, rapid parallel synthesis of compound libraries, and library generation by automated sequential microwave irrad... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481719 Sat, 01 Dec 2007 05:00:00 +0100 1481719 http://www.medworm.com/index.php?rid=1481718&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18288950%26dopt%3DAbstract Authors: Besson T, Chosson E This paper aims to review recent developments in the synthesis of quinazolines and quinazolinone derivatives under conditions that include the application of microwave heating in the ring forming step. Recently, two reviews on the synthesis and chemistry of natural and synthetic quinazolines and quinazolinones have been published. This review highlights significant examples where microwave heating has been either synthetically enabling or has provided a key advantage over conventional thermal methods. Wherever possible, this review will focus on chemistry carried out using monomode systems and well-designed type of instrumentation. The review is grouped according to the main heterocycle types in order of increasing complexity; commencing with quinazolines a... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481718 Sat, 01 Dec 2007 05:00:00 +0100 1481718 http://www.medworm.com/index.php?rid=1481717&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18288951%26dopt%3DAbstract Authors: Alcázar J, Dielsb G, Schoentjes B The blending of microwave heating and parallel chemistry is a logical consequence of the significant rate enhancement and higher product yield afforded by microwave technology and the increase in productivity afforded by combinatorial chemistry. For this reason, this combination has become increasingly popular in the organic chemistry community. The current review highlights the application of this approach as a way to increase the rate of analogue synthesis in medicinal chemistry. PMID: 18288951 [PubMed - indexed for MEDLINE] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481717 Sat, 01 Dec 2007 05:00:00 +0100 1481717 http://www.medworm.com/index.php?rid=1481692&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18478955%26dopt%3DAbstract Authors: Díaz-Ortiz A, del la Hoz A PMID: 18478955 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481692 Thu, 01 Nov 2007 04:00:00 +0100 1481692 http://www.medworm.com/index.php?rid=1481691&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18478956%26dopt%3DAbstract Authors: Kappe CO, Matloobi M Microwave-assisted organic synthesis is an enabling technology that has been exploited for a variety of applications including medicinal chemistry/drug discovery projects where speed is often a critical factor. In this review, applications of microwave-assisted organic synthesis employing a parallel processing regime are summarized. Examples include parallel synthesis in domestic microwave ovens, the use of specialized multivessel rotors and microtiter plates in dedicated multimode microwave reactors, and applications of SPOT synthesis on cellulose matrices. PMID: 18478956 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481691 Thu, 01 Nov 2007 04:00:00 +0100 1481691 http://www.medworm.com/index.php?rid=1481690&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18478957%26dopt%3DAbstract Authors: Sandoval WN, Pham V, Ingle ES, Liu PS, Lill JR Biotechnology has recently celebrated 30 years both as a science and as a multi-billion dollar industry. One application of biotechnology is to use human genetic information to discover, develop, manufacture, and commercialize biotherapeutics. Recombinant proteins can be produced in large quantities at high purity. High-throughput proteomic analysis is at the heart of the biotechnology research and development process, and the industry is constantly striving to streamline and automate the analytical processes involved. Microwave-assisted proteomics has recently emerged as a tool for increasing the bio-catalysis of several processes including tryptic digestions lipase selectivities, identification of metal-catalyzed oxidation sites... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481690 Thu, 01 Nov 2007 04:00:00 +0100 1481690 http://www.medworm.com/index.php?rid=1481689&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18478958%26dopt%3DAbstract Authors: Langa F, de la Cruz P Microwave irradiation is an important tool in the functionalization of fullerenes and carbon nanotubes. These are compounds with excellent properties that make them useful for the development of optoelectronic organic devices. The applications of microwaves in the chemistry of these materials are reviewed. PMID: 18478958 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481689 Thu, 01 Nov 2007 04:00:00 +0100 1481689 http://www.medworm.com/index.php?rid=1481688&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18478959%26dopt%3DAbstract Authors: Lagerlund O, Odell LR, Mowbray SL, Nilsson MT, Krajewski WW, Nordqvist A, Karlén A, Larhed M A microwave-enhanced, palladium-catalyzed protocol for the alpha-arylation of a protected glycine in neat water is described. This reaction proceeds rapidly, under non-inert conditions, to afford a range of phenylglycine derivatives in moderate to good yields. Based on this alpha-arylation, a number of aryl L-methionine-SR-sulfoximine (MSO) analogues were prepared and evaluated for their Mycobacterium tuberculosis glutamine synthetase (TB-GS) inhibitory activity. PMID: 18478959 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481688 Thu, 01 Nov 2007 04:00:00 +0100 1481688 http://www.medworm.com/index.php?rid=1481687&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18478960%26dopt%3DAbstract Authors: Appukkuttan P, Dehaen W, Van der Eycken E Microwave-assisted Suzuki-Miyaura and Stille cross-coupling reactions for the synthesis of highly electron-rich and diversely functionalized biaryl intermediates are presented. Microwave-irradiation has been demonstrated to be a very powerful tool for performing difficult transition metal-catalyzed cross-coupling reactions with unfavorably substituted coupling partners. The key biaryl intermediates were used for the microwave-enhanced construction of the 5,6,7,8-tetrahydrobenzo[c,e]azocine skeleton of the Apogalanthamine analogs. The success of the strategy is demonstrated by synthesizing a number of hitherto unknown, diversely functionalized, natural product analogs. PMID: 18478960 [PubMed - in process] (Source: Combinatorial Chem... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481687 Thu, 01 Nov 2007 04:00:00 +0100 1481687 http://www.medworm.com/index.php?rid=1481737&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18045076%26dopt%3DAbstract Authors: Bharucha N, Kumar A The budding yeast Saccharomyces cerevisiae is well recognized as a preferred eukaryote for the development of genomic technologies and approaches. Accordingly, a sizeable complement of genomic resources has been developed in yeast, and this genomic foundation is now informing a wide variety of disciplines. In particular, yeast genomic methodologies are gaining an expanding foothold in drug development studies, most notably as a preliminary tool towards drug target identification. In this review, we highlight many applications of yeast genomics in the identification of targeted genes and pathways of small molecules or therapeutic drugs. The applicability of genome-wide resources of yeast disruption and deletion mutants for drug-sensitivity/resistance screeni... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481737 Sat, 01 Sep 2007 04:00:00 +0100 1481737 http://www.medworm.com/index.php?rid=1481736&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18045077%26dopt%3DAbstract Authors: Fang YQ, Wong WQ, Yap YW, Orner BP Stem cell-based technologies have the potential to help cure a number of cell degenerative diseases. Combinatorial and high throughput screening techniques could provide tools to control and manipulate the self-renewal and differentiation of stem cells. This review chronicles historic and recent progress in the stem cell field involving both pluripotent and multipotent cells, and it highlights relevant cellular signal transduction pathways. This review further describes screens using libraries of soluble, small-molecule ligands, and arrays of molecules immobilized onto surfaces while proposing future trends in similar studies. It is hoped that by reviewing both the stem cell and the relevant high throughput screening literature, this paper ca... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481736 Sat, 01 Sep 2007 04:00:00 +0100 1481736 http://www.medworm.com/index.php?rid=1481735&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18045078%26dopt%3DAbstract Authors: Krishnamurty R, Maly DJ The clinical success of the Bcr-Abl tyrosine kinase inhibitor Gleevec((R)) and the recent clinical approval of a number of small molecule drugs that target protein kinases have intensified the search for novel protein kinase inhibitors. Since most small molecule kinase inhibitors target the highly conserved ATP-binding pocket of this enzyme family, the target selectivity of these molecules is a major concern. Due to the large size of the human kinome, it is a formidable challenge to determine the absolute specificity of a given protein kinase inhibitor, but recent technological developments have made substantial progress in achieving this goal. This review summarizes some of the most recent experimental techniques that have been developed for the determ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481735 Sat, 01 Sep 2007 04:00:00 +0100 1481735 http://www.medworm.com/index.php?rid=1481734&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18045079%26dopt%3DAbstract Authors: Gestwicki JE, Marinec PS Protein-protein interactions have become attractive drug targets and recent studies suggest that these interfaces may be amenable to inhibition by small molecules. However, blocking specific interactions may not be the only way of manipulating the extensive network of interacting proteins. Recently, several approaches have emerged for promoting these interactions rather than inhibiting them. Typically, these strategies employ a bifunctional ligand to simultaneously bind two targets, forcing their juxtaposition. Chemically "riveting" specific protein contacts can reveal important aspects of regulation, such as the consequences of stable dimerization or the effects of prolonged dwell time. Moreover, in some cases, entirely new functions arise when two pr... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481734 Sat, 01 Sep 2007 04:00:00 +0100 1481734 http://www.medworm.com/index.php?rid=1481733&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18045080%26dopt%3DAbstract Authors: Powers R The recent success of the human genome project and the continued accomplishment in obtaining DNA sequences for a vast array of organisms is providing an unprecedented wealth of information. Nevertheless, an abundance of the proteome contains hypothetical proteins or proteins of unknown function, where high throughput approaches for genome-wide functional annotation (functional genomics) has evolved as the necessary next step. Nuclear magnetic resonance spectroscopy is playing an important role in functional genomics by providing information on the structure of protein and protein-ligand complexes, from metabolite fingerprinting and profiling, from the analysis of the metabolome, and from ligand affinity screens to identify chemical probes. PMID: 18045080 [PubMed -... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481733 Sat, 01 Sep 2007 04:00:00 +0100 1481733 http://www.medworm.com/index.php?rid=1481732&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18045081%26dopt%3DAbstract Authors: Srivatsan SG, Famulok M In vitro selection can be used to generate functional nucleic acids such as aptamers and ribozymes that can recognize a variety of molecules with high affinity and specificity. Most often these recognition events are associated with structural alterations that can be converted into detectable signals. Several signaling aptamers and ribozymes constructed by both design and selection have been successfully utilized as sensitive detection reagents. Here we summarize the development of different types of signaling nucleic acids, and approaches that have been implemented in the screening format. PMID: 18045081 [PubMed - indexed for MEDLINE] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481732 Sat, 01 Sep 2007 04:00:00 +0100 1481732 http://www.medworm.com/index.php?rid=1481731&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18045082%26dopt%3DAbstract Authors: Tao SC, Chen CS, Zhu H Protein microarrays, an emerging class of proteomic technologies, are quickly becoming essential tools for large-scale and high throughput biochemistry and molecular biology. Recent progress has been made in all the key steps of protein microarray fabrication and application, such as the large-scale cloning of expression-ready prokaryotic and eukaryotic ORFs, high throughput protein purification, surface chemistry, protein delivery systems, and detection methods. Two classes of protein microarrays are currently available: analytical and functional protein microarrays. In the case of analytical protein microarrays, well-characterized molecules with specific activity, such as antibodies, peptide-MHC complexes, or lectins, are used as immobilized probes. Th... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481731 Sat, 01 Sep 2007 04:00:00 +0100 1481731 http://www.medworm.com/index.php?rid=1481730&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D18045083%26dopt%3DAbstract Authors: Bender A, Young DW, Jenkins JL, Serrano M, Mikhailov D, Clemons PA, Davies JW Chemogenomics comprises a systematic relationship between targets and ligands that are used as target modulators in living systems such as cells or organisms. In recent years, data on small molecule-bioactivity relationships have become increasingly available, and consequently so have the number of approaches used to translate bioactivity data into knowledge. This review will focus on two aspects of chemogenomics. Firstly, in cases such as cell-based screens, the question of which target(s) a compound is modulating in order to cause the observed phenotype is crucial. In silico target prediction tools can suggest likely biological targets of small molecules via data mining in target-annotated chemical... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481730 Sat, 01 Sep 2007 04:00:00 +0100 1481730 http://www.medworm.com/index.php?rid=1481749&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17979633%26dopt%3DAbstract Authors: Bazylak G PMID: 17979633 [PubMed - indexed for MEDLINE] (Source: Combinatorial Chemistry and High Throughput Screening) Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481749 Wed, 01 Aug 2007 04:00:00 +0100 1481749 http://www.medworm.com/index.php?rid=1481748&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17979634%26dopt%3DAbstract Authors: Uslu B, Ozkan SA This review summarizes recent progress in the development and application of solid electrodes to the screening of pharmaceutical dosage forms and biological fluids. Recent trends and advances in the electroanalytical chemistry of solid electrodes, microelectrodes and electrochemical sensors are reviewed. The varieties of solid electrodes and their basic physico-chemical properties and some specific characteristics including some supramolecular phenomena at their surface are surveyed. This review also includes some selected designs and their applications. Despite many reviews about individual solid electrodes in the literature, this review offers the first comprehensive report on all forms of solid electrodes. Special attention is paid to the possibilities of s... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481748 Wed, 01 Aug 2007 04:00:00 +0100 1481748 http://www.medworm.com/index.php?rid=1481747&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17979635%26dopt%3DAbstract Authors: Gulaboski R, Borges F, Pereira CM, Cordeiro MN, Garrido J, Silva AF The latest results of voltammetric research on the ionic transfer process of ionisable drugs across bare and lipid-modified liquid-liquid interfaces are reviewed. In recent years, two voltammetric methods have been extensively applied to this purpose, i.e. the classical four electrode voltammetry at the interface between two immiscible electrolyte solutions, and the "three-phase electrode." Thus, a brief background of the methodologies and some successful examples of their application are highlighted in this work. Particular attention is given to the ionic transfer kinetics and to the electrochemical characterization of the drug-membrane interactions between the ionized drugs and lipid-modified interfaces. Fut... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481747 Wed, 01 Aug 2007 04:00:00 +0100 1481747 http://www.medworm.com/index.php?rid=1481746&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17979636%26dopt%3DAbstract Authors: Faridbod F, Ganjali MR, Dinarvand R, Norouzi P Schiff base compounds refer to the branch of supra-molecules and can be used as sensing material in the construction of potentiometric ion selective electrodes (ISEs). This relatively modern field has been subject to extensive research in the period of 1999-2007 when more than 100 ISEs employing Schiff bases were constructed. The quantitative high-throughput detection of 29 cations and 7 anions has been demonstrated in various scientific branches, such as biomedicine, pharmacy, biochemistry, pharmacology, environmental chemistry, food technology, and agriculture. This review discusses Schiff base compounds and their applications in the design and development of ion selective sensors and microsensors. PMID: 17979636 [PubMed - i... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481746 Wed, 01 Aug 2007 04:00:00 +0100 1481746 http://www.medworm.com/index.php?rid=1481745&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17979637%26dopt%3DAbstract Authors: Wang C, Xu J, Zhou G, Qu Q, Yang G, Hu X Recent advances in electrochemical detection techniques coupled with high-performance liquid chromatography (HPLC-ECD) in pharmaceutical and biomedical analysis are reviewed. ECD classification and modes including common amperometric, coulometric, conductimetric, and potentiometric detector, are outlined and the some typical examples of determinations in pharmaceutical and biomedical analysis are described. The electrochemical detection system can offer superior merits over other detectors commonly used with HPLC. These techniques have great potential owing to their prominent characteristics in high-throughput screening procedures of drugs in various matrices. Fundamental 67 references from last 5 years related with a field are cited in... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481745 Wed, 01 Aug 2007 04:00:00 +0100 1481745 http://www.medworm.com/index.php?rid=1481744&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17979638%26dopt%3DAbstract Authors: Nagels LJ, Everaert J, Bohets H, Del Favero J, Goossens D, Robbens J, Pietraszkiewicz M, Pietraszkiewicz O Potentiometric sensors are studied as viable candidates for the construction of high throughput DNA arrays. For preliminary investigations, such sensors were used in an HPLC setup in the present work. This avoided errors due to ionic contaminants or additives in the commercial samples. The oligonucleotides dT(10), dT(20) and dT(30) were used as test substances. The potentiometric sensors were of the coated wire type, containing PVC, DOP, MTDDACl and a synthetic podand urea receptor. The HPLC system consisted of a reversed phase column eluted with a phosphate buffer, triethylammoniumacetate (TEAA), and an acetonitrile gradient. Molar responses and sensitivities increased w... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481744 Wed, 01 Aug 2007 04:00:00 +0100 1481744 http://www.medworm.com/index.php?rid=1481743&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17979639%26dopt%3DAbstract Authors: Gupta VK, Singh AK, Gupta B The construction and characterization of potentiometric membrane electrodes are described for the quantification of alfuzosin, a drug used in a mono- and combined therapy of benign prostatic hyperplasia (BPH). The membranes of these electrodes consist of alfuzosin hydrochloride-tetraphenyl borate, (Az-TPB), chlorophenyl borate (Az-ClPB), and phosphotungstate (Az(3)-PT) ion associations as molecular recognition reagent dispersed in PVC matrix with dioctylpthalate as plasticizer. The performance characteristics of these electrodes, which were evaluated according to IUPAC recommendations, revealed a fast, stable and liner response for alfuzosin over the concentration ranges of 8.3 x 10(-6) to 1.0 x 10(-2) M, 3.8 x 10(-6) to 1.0 x 10(-2) M, 7.5 x 10(-7)... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481743 Wed, 01 Aug 2007 04:00:00 +0100 1481743 http://www.medworm.com/index.php?rid=1481742&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17979640%26dopt%3DAbstract Authors: Dogan-Topal B, Uslu B, Ozkan SA The electrochemical behavior of atorvastatin calcium at glassy carbon and boron-doped diamond electrodes has been studied using voltammetric techniques. The possible mechanism of oxidation was discussed with model compounds. The dependence of the peak current and potentials on pH, concentration, scan rate and nature of the buffer were investigated for both electrodes. The oxidation of atorvastatin was irreversible and exhibited a diffusion-controlled fashion on the diamond electrode. A linear response was obtained within the range of 9.65 x 10(-7) - 3.86 x 10(-5) M in 0.1 M H(2)SO(4) solution for both electrodes. The detection limits of a standard solution are estimated to be 2.11 x 10(-7) M with differential pulse voltammetry (DPV) and 2.05 x 1... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481742 Wed, 01 Aug 2007 04:00:00 +0100 1481742 http://www.medworm.com/index.php?rid=1481741&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17979641%26dopt%3DAbstract Authors: Gupta VK, Singh AK, Gupta B The electrochemical response characteristics of poly(vinyl)chloride (PVC) based membrane sensors for determination of tetramisole hydrochloride (TmCl) is described. The membranes of these electrodes consist of tetramisole-tetraphenyl borate (Tm-TPB), chlorophenyl borate (Tm-ClPB), and phosphotungstate (Tm(3)-PT) ion associations dispersed in a PVC matrix with dibutylpthalate as a plasticizer. The electrodes were fully characterized in terms of composition, life span, usable pH range, and working concentration range and ionic strength. The electrodes showed Nernstian response over the concentration ranges of 7.4 x 10(-7) to 1.0 x 10(-2) M, 1.7 x 10(-6) to 1.0 x 10(-2) M, and 5.6 x 10(-6) to 1.0 x 10(-2) M TmCl, respectively, and were applied to the p... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481741 Wed, 01 Aug 2007 04:00:00 +0100 1481741 http://www.medworm.com/index.php?rid=1481740&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17979642%26dopt%3DAbstract Authors: Wang C, Guan J, Qu Q, Yang G, Hu X Polycysteic acid based electrochemical oxidation of L-cysteine (CySH) and carbon nanotubes (CNTs) formed a composite thin film material at a glassy carbon electrode (GCE) that was used a novel modifier for electroanalytical determination of sinomenine which is used for rheumatoid arthritis treatment. The determination of sinomenine at the composite modified electrode was studied by differential pulse voltammetry (DPV). The peak current obtained at + 0.632 V (vs SCE) from DPV was linearly dependent on the sinomenine concentration in the range of 1.0 x 10(-7) to 6.0 x 10(-5) M in a B-R buffer solution (0.04 M, pH 1.81) with a correlation coefficient of 0.998. The detection limit (S/N = 3) was 5.0 x 10(-8) M. The electrochemical reaction mechani... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481740 Wed, 01 Aug 2007 04:00:00 +0100 1481740 http://www.medworm.com/index.php?rid=1481739&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17979643%26dopt%3DAbstract Authors: Kurzatkowska K, Radecka H, Dehaen W, Wasowicz M, Grzybowska I, Radecki J The PVC supported liquid membrane electrodes incorporated with undecylcalix[4]resorcinarene (UDC[4]Rene) generates a cationic potentiometric response after stimulation by neutral (unprotonated) form of diaminobenzene isomers. The potentiometric signals were generated upon the formation of supramolecular complex between the UDC[4]Rene (host) and diaminobenzene (guest) at the organic-aqueous interface. In this paper for the first time we report the generation of cationic potential signal by electrode incorporated with host molecule possessing oxygen as a heteroatom, after stimulation with neutral guest containing nitrogen in its structure We also broaden the family of receptor molecules, which are able to g... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481739 Wed, 01 Aug 2007 04:00:00 +0100 1481739 http://www.medworm.com/index.php?rid=1481738&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17979644%26dopt%3DAbstract Authors: Ali I, Aboul-Enein HY, Gupta VK An inexpensive, rapid and reproducible capillary electrophoretic method has been developed and validated for the determination of metformin in pharmaceutical preparations. The method was developed utilizing a fused silica capillary (60 cm x 50 microm I.D.), phosphate buffer (50 mM, 3.0 pH)-acetonitrile (95:5, v/v) as background electrolyte (BGE), 20 kV applied voltage with UV detection at 254 nm and at a working temperature of 23 +/- 1 degrees C. Linearity was observed in the concentration range from 100 ng/L to 5 microg/L, with a correlation coefficient (R2) of 0.9998. The limits of detection and quantification achieved were 60 and 100 ng/mL, respectively. The recovery of metformin from pharmaceutical preparations was 99.1%. These validation pa... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481738 Wed, 01 Aug 2007 04:00:00 +0100 1481738 http://www.medworm.com/index.php?rid=1481759&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17896936%26dopt%3DAbstract Authors: Achyuthan KE, Whitten DG This paper reviews the several different factors that must be considered during the development of assays for high throughput screening (HTS) or in vitro diagnostic (IVD) applications. The reader is introduced to the terminology used in assay development as well as the statistical approaches for evaluating the data. The review is intended to serve as a tutorial to biotechnology, pharmaceutical and clinical professionals, the academic researcher, as well as a guide for established investigators of HTS and IVD. This review is not a comprehensive treatise in its scope or content, but is meant to introduce the reader to key concepts of assay development. Elementary mathematical and statistical tools for designing robust assays and data management are descr... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481759 Sun, 01 Jul 2007 04:00:00 +0100 1481759 http://www.medworm.com/index.php?rid=1481758&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17896937%26dopt%3DAbstract Authors: Bosch ME, Sánchez AJ, Rojas FS, Ojeda CB Optical biosensors have been commercially available since the early 1990s, and have been used extensively in many areas of research in the life sciences. Optical biosensors developed for drug analysis generally exploit the high selectivity of the antigen-antibody and drug-protein interaction. Optical biosensors can be made based on optical diffraction or electro-chemiluminescence. High-throughput screening, (HTS) which includes automated preparation of a large number of samples and then screening of their properties in multi-well plates, improves the efficiency of research in many scientific areas, e.g., catalyst screening, food processing, chemical synthesis, drug discovery, absorption, distribution, metabolism, and excretion and ... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481758 Sun, 01 Jul 2007 04:00:00 +0100 1481758 http://www.medworm.com/index.php?rid=1481757&cid=s_37005_59_f&fid=37005&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D17896938%26dopt%3DAbstract Authors: Bertucci C, Piccoli A, Pistolozzi M Specific molecular interactions provide a fundamental mechanism for selectivity in every aspect of biological structure and function. The ability to measure quantitatively such interaction properties across a wide range of affinity, size, and purity is a growing need. A short review on the use of the optical biosensor techniques is presented, focused on its application for determining the absorption and distribution parameters of drugs and lead compounds. The basic biosensor technology principles are described together with some immobilization methods commonly used for the preparation of selective and specific biosensor surfaces for assays. Some relevant research topics in the field of small molecule recognition phenomena are presented as ex... Combinatorial Chemistry and High Throughput Screening journals http://www.medworm.com/rss/comments.php?id=1481757 Sun, 01 Jul 2007 04:00:00 +0100 1481757