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 'Chemical Biology and Drug Design' source. Sun, 21 Mar 2010 17:00:40 +0100 http://www.medworm.com/index.php?rid=3385093&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00961.x A better understanding of the metabolic adaptations of the vascular endothelial cells (EC) that mediate tumor vascularization would help the development of new drugs and therapies. Novel roles in cell survival and metabolic adaptation to hypoxia have been ascribed to the microsomal glucose-6-phosphate translocase (G6PT). While antitumorigenic properties of G6PT inhibitors such as chlorogenic acid (CHL) have been documented, those of the G6PT inhibitor and semi-synthetic analog AD4-015 of the polyketide mumbaistatin are not understood. In the present study, we evaluated the in vitro antiangiogenic impact of AD4-015 on human brain microvascular endothelial cells (HBMEC), which play an essential role as structural and functional components in tumor angiogenesis. We found that in vitro HBMEC m... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3385093 Sat, 20 Mar 2010 00:00:00 +0100 3385093 http://www.medworm.com/index.php?rid=3385096&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00963.x The novel amides of ketoprofen and its reduced derivatives (5a[ndash]f, 4a[ndash]n, 6a[ndash]g) with aromatic and cycloalkyl amines or hydroxylamines were prepared and screened for their reducing and cytostatic activity as well as for their ability to inhibit soybean lipoxygenase and lipid peroxidation. 1,1-Diphenyl-picrylhydrazyl test for reducing ability revealed that ketoprofen amides were more potent antioxidants than the amides of the reduced ketoprofen derivatives. The most active compound was benzhydryl ketoprofen amide 5f. Lipoxygenase inhibition of the tested compounds varied from strong to very weak. The most potent compound was benzhydryl derivative 6f (IC50 = 20.5 [mu]m). Aromatic and cycloalkyl amides 4 and 5 were more potent lipoxygenase inhibitors than derivatives with carbo... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3385096 Fri, 19 Mar 2010 00:00:00 +0100 3385096 http://www.medworm.com/index.php?rid=3385095&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00953.x The support vector machine (SVM) and partial least square (PLS) methods were used to develop quantitative structure activity relationship (QSAR) models to predict the inhibitory activity of non-peptide HIV-1 protease inhibitors. Genetic algorithm (GA) was employed to select variables that lead to the best-fitted models. A comparison between the obtained results using SVM with those of PLS revealed that the SVM model is much better than that of PLS. The root mean square errors of the training set and the test set for SVM model were calculated to be 0.2027, 0.2751, and the coefficients of determination (R2) are 0.9800, 0.9355 respectively. Furthermore, the obtained statistical parameter of leave-one-out cross-validation test (Q2) on SVM model was 0.9672, which proves the reliability of this ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3385095 Fri, 19 Mar 2010 00:00:00 +0100 3385095 http://www.medworm.com/index.php?rid=3385094&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00960.x Quantitative structure activity relationship (QSAR) analyses using a novel type of electronic descriptors called quantum topological molecular similarity (QTMS) indices were operated to describe and compare the mechanisms of toxicity of phenols toward five different strains (i.e., Tetrahymena pyriformis, L1210 Leukemia, Pseudomonas putida, Raja japonica and Cucumis sativus). The appropriate QSAR models for the toxicity data were obtained separately employing partial least squares (PLS) regression combined with genetic algorithms (GA), as a variable selection method. The resulting QSAR models were used to identify molecular fragments of phenol derivatives whose electronic properties contribute significantly to the observed toxicities. Using this information, it was feasible to discriminate ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3385094 Fri, 19 Mar 2010 00:00:00 +0100 3385094 http://www.medworm.com/index.php?rid=3358294&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00955.x Transcription factor Nrf2 regulates a battery of genes encoding detoxifying enzymes. Under basal conditions, Nrf2 is sequestered in the cytoplasm by a protein known as Keap1. In response to oxidative stress, Keap1-mediated ubiquitination of Nrf2 is decreased significantly and the Nrf2 pathway is turned on. Residues C273 and C288 at the intervening region (IVR) domain of Keap1 are necessary for Keap1 to repress Nrf2, indicating a critical role of the IVR domain in the functional interaction of Keap1 with Nrf2. To identify chemical modulator targeting the IVR domain of Keap1, we built a 3D structural model of the Keap1 IVR domain and demonstrated this structural model is effective in retrieving novel Nrf2 inducers from chemical databases, BM10, 31, and 40 increase concentration of nuclear Nr... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3358294 Fri, 12 Mar 2010 00:00:00 +0100 3358294 http://www.medworm.com/index.php?rid=3358293&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00958.x Considering the fact that majority of support vector regression models have not been fully optimized in the realm of quantitative structure-activity relationship, an idea of simultaneous optimization has been proposed and evaluated on a set of novel kinase insert domain receptor/vascular endothelial growth factor receptor-2 inhibitors including naphthalene and indazole-based compounds in this study. After the powerful feature searching process using genetic algorithm, the final support vector regression model was constructed on an optimal set of six descriptors, based on which simultaneous optimization was carried out. Specifically, the global optimum is grid searched in the joint parametric space defined by cost (C), [gamma] and [epsilon], where performance of support vector regression us... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3358293 Fri, 12 Mar 2010 00:00:00 +0100 3358293 http://www.medworm.com/index.php?rid=3358292&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00962.x We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3). Hydrolysis of the methyl ester adduct (5) yielded the free acid (6). The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3358292 Fri, 12 Mar 2010 00:00:00 +0100 3358292 http://www.medworm.com/index.php?rid=3358291&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00950.x Tumor necrosis factor alpha is one of the most common pro-inflammatory cytokines responsible for various inflammatory disorders. It plays an important role in the origin and progression of rheumatoid arthritis and also in other autoimmune disease conditions. Some anti-tumor necrosis factor alpha antibodies like Enbrel®, Humira® and Remicade® have been successfully used in these disease conditions as antagonists of tumor necrosis factor alpha. Inhibition of generation of active form of tumor necrosis factor alpha is a promising therapy for various inflammatory disorders. Therefore, the inhibition of an enzyme (tumor necrosis factor alpha converting enzyme), which is responsible for processing inactive form of tumor necrosis factor alpha into its active soluble form, is an encouraging tar... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3358291 Fri, 12 Mar 2010 00:00:00 +0100 3358291 http://www.medworm.com/index.php?rid=3353713&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00965.x The inhibitory effects of some phenolic acids on the cytosolic human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes hCA I and hCA II were investigated. Ellagic acid, gallic acid, ferulic acid, caffeic acid, quercetin, p-coumaric acid, p-hydroxybenzoic acid, and syringic acid showed KI values in the range of 99[ndash]1061 [mu]m for hCA I and of 105[ndash]758 [mu]m against hCA II, respectively. Quercetin (for hCA I), p-coumaric acid (for hCA II), and gallic acid (for hCA II) exhibited competitive inhibitory effects with 4-nitrophenyl acetate as substrate. All of the other phenolic acids were found as non-competitive inhibitors with 4-nitrophenylacetate as substrate for hCA I and hCA II. The phenolic acids investigated here showed thus interesting hCA I and hCA II inhibitory effects and might ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3353713 Thu, 11 Mar 2010 00:00:00 +0100 3353713 http://www.medworm.com/index.php?rid=3353717&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00954.x Peptides are labile toward proteolytic enzymes, and structural modifications are often required to prolong their metabolic half-life and increase resistance. One modification is the incorporation of non-[alpha]-amino acids into the peptide to deter recognition by hydrolytic enzymes. We previously reported the synthesis of chimeric [alpha]/[delta]-peptides from glutamic acids (Glu) and the sialic acid derivative Neu2en. Conformational analyses revealed these constructs adopt secondary structures in water and may serve as conformational surrogates of polysialic acid. Polysialic acid is a tumor-associated polysaccharide and is correlated with cancer metastasis. Soluble polysialic acid is rapidly cleared from the blood limiting its potential for vaccine development. One motivation in developin... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3353717 Wed, 10 Mar 2010 00:00:00 +0100 3353717 http://www.medworm.com/index.php?rid=3353716&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00957.x We describe application of these tools to a series of 9-oxo-4,9-dihydropyrazolo[5,1-b]quinazoline-2-carboxylic acids (PQ) hits from a screen of Escherichia coli phosphopantetheine adenylyltransferase (PPAT). Initial confirmation of specific binding to phosphopantetheine adenylyltransferase was obtained using biochemical and biophysical tools, including a novel orthogonal assay, isothermal titration calorimetry, and saturation transfer difference NMR. To identify the phosphopantetheine adenylyltransferase sub-site bound by these inhibitors, two techniques were utilized: steady-state enzyme kinetics and a novel 19F NMR method in which fluorine-containing fragments that bind the ATP and/or phosphopantetheine sites serve as competitive reporter probes. These data are consistent with PQs bindin... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3353716 Wed, 10 Mar 2010 00:00:00 +0100 3353716 http://www.medworm.com/index.php?rid=3353715&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00959.x Two types of regioisomeric chromene-based chalcones namely, 1-(6-methoxy-2H-chromen-3-yl)-3-phenylpropen-1-ones and 3-(6-methoxy-2H-chromen-3-yl)-1-phenylpropen-1-ones were prepared and investigated for their antileishmanial activity against promastigotes form of Leishmania major. The obtained results from in vitro biological assays indicated that chloro-substituted 1-(6-methoxy-2H-chromen-3-yl)-3-phenylpropen-1-ones exhibited excellent activity against Leishmania major at non-cytotoxic concentrations. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3353715 Wed, 10 Mar 2010 00:00:00 +0100 3353715 http://www.medworm.com/index.php?rid=3353714&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00964.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3353714 Wed, 10 Mar 2010 00:00:00 +0100 3353714 http://www.medworm.com/index.php?rid=3297788&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00949.x The tumor suppressor gene, SMAD4, is mutated in approximately 30% of colon cancers. To identify compounds with enhanced potency on cells with a SMAD4-negative context, we combined genomic and cheminformatic analyses of publicly available data relating to the colon cancer cell lines within the NCI60 panel. Two groups of cell lines were identified with either wild-type or negative SMAD4 status. A cheminformatic analysis of the NCI60 screening data was carried out, which led to the identification of 14 compounds that preferentially inhibited cell growth of the SMAD4-negative cell lines. Using cell viability assays, the effect of these compounds was validated on four colon cancer cell lines: HCT-116 and HCT-15 (SMAD4-expressing), and HT-29 and COLO-205 (SMAD4-negative). Our data identified Mac... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3297788 Mon, 22 Feb 2010 00:00:00 +0100 3297788 http://www.medworm.com/index.php?rid=3297787&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00951.x Reactivation of the p53 cell apoptosis pathway through inhibition of the p53-hDM2 interaction is a viable approach to suppress tumor growth in many human cancers and stabilization of the helical structure of synthetic p53 analogs via a hydrocarbon cross-link (staple) has been found to lead to increased potency and inhibition of protein[ndash]protein binding (J. Am. Chem. Soc. 129: 5298). However, details of the structure and dynamic stability of the stapled peptides are not well understood. Here, we use extensive all-atom molecular dynamics simulations to study a series of stapled [alpha]-helical peptides over a range of temperatures in solution. The peptides are found to exhibit substantial variations in predicted [alpha]-helical propensities that are in good agreement with the experiment... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3297787 Mon, 22 Feb 2010 00:00:00 +0100 3297787 http://www.medworm.com/index.php?rid=3262203&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00952.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3262203 Thu, 11 Feb 2010 00:00:00 +0100 3262203 http://www.medworm.com/index.php?rid=3253893&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00947.x Twenty four novel 2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetic acid amides were synthesized from phthalic anhydride and were subjected to in vitro and in vivo evaluation against log- and starved phase of mycobacterial species and Mycobacterium tuberculosis isocitrate lyase enzyme inhibition studies. Among the compounds screened, 2-(2-(4-bromo-2-fluorobenzyl)-1,2-dihydro-1-oxophthalazin-4-yl)-N-(2,6-dimethylphenyl)acetamide (5j) inhibited all eight mycobacterial species with MIC's ranging from 0.08 to 5.05 [mu]m and was non-toxic to Vero cells till 126.43 [mu]m. Four compounds were tested against starved culture of Mycobacterium tuberculosis and they inhibited with MIC's ranging from 3.78 to 23.2 [mu]m. Some compounds showed 40[ndash]66% inhibition against Mycobacte... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3253893 Tue, 09 Feb 2010 00:00:00 +0100 3253893 http://www.medworm.com/index.php?rid=3253894&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2010.00946.x Riboflavin (vitamin B2) is the direct precursor of redox enzyme cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are essential for multiple cell physiology. The riboflavin biosynthetic pathway is regarded as a rich resource for therapeutic targets for broad spectrum antibiotics. Enzymatic pathways, regulatory factors of the riboflavin biosynthesis, and relevant drug discovery are summarized in this review. The novel riboswitch regulatory mechanism of riboflavin metabolism is also described. A compendium of chemical modulators of riboflavin biosynthesis and regulatory networks is listed and such demonstrates the promise of riboflavin biosynthesis and regulatory mechanisms as potential therapeutic targets for novel antibiotic drug discovery. (Source: Chemica... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3253894 Mon, 08 Feb 2010 00:00:00 +0100 3253894 http://www.medworm.com/index.php?rid=3184871&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00922.x This article deals with the synthesis of various simplified vinca alkaloids, using a stereoselective coupling of catharantine with reactive aromatic compounds and methanol as well as their subsequent condensation with a large peptide chain mimicking those of phomopsin A. Biological evaluation and molecular modeling studies are also reported. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3184871 Tue, 19 Jan 2010 00:00:00 +0100 3184871 http://www.medworm.com/index.php?rid=3184870&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00932.x A series of 2-[2-(aroyl-aroxy)-methyl]-4-phenyl-1,3-thiazoles 4a[ndash]j were obtained via multiple step synthesis sequence beginning with the hydroxybenzophenones (1a[ndash]g). Hydroxybenzophenones on reaction with chloroacetonitrile affords [(2-benzoyl) phenoxy] acetonitrile (2a[ndash]g), which reacts with H2S/NH4OH and yields [(2-benzoyl) phenoxy] acetothiamide (3a[ndash]g), which on treatment with phenacylbromides affords 2-[2-(aroyl-aroxy)-methyl]-4-phenyl-1,3-thiazoles (4a[ndash]j). All the newly synthesized compounds were evaluated for their anti-inflammatory activity and were compared with standard drugs. Of the compounds studied, (4g), compounds with chloro substituents showed more potent activity than the standard drug phenyl butazone at all doses tested. (Source: Chemical Biolog... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3184870 Tue, 19 Jan 2010 00:00:00 +0100 3184870 http://www.medworm.com/index.php?rid=3184869&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00933.x Acetophenones were screened for activity against positive phototaxis of Chlamydomonas cells, a process that requires co-ordinated flagellar motility. The structure[ndash]activity relationships of a series of acetophenones are reported, including acetophenones that affect flagellar motility and cell viability. Notably, 4-methoxyacetophenone, 3,4-dimethoxyacetophenone, and 4-hydroxyacetophenone induced negative phototaxis in Chlamydomonas, suggesting interference with activity of flagellar proteins and control of flagellar dominance. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3184869 Tue, 19 Jan 2010 00:00:00 +0100 3184869 http://www.medworm.com/index.php?rid=3184868&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00936.x The interleukin 6 receptor (IL-6R) and its ligand interleukin 6 (IL-6) play a crucial role in glioma growth and development accomplished by autocrine growth promotion and induction of angiogenesis via activation of vascular epithelial growth factor A (VEGF-A). Therefore, IL-6R represents a target for both therapy (preventing VEGF-A activation by blocking the receptor) and imaging (higher receptor density on tumor cells). A short heptapeptide that selectively binds to IL-6R and which inhibits the effect of IL-6 was coupled to the magnetic resonance imaging (MRI) contrast agent gadolinium (Gd)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and the fluorescent dye rhodamine. MRI, confocal laser scanning microscopy, and flow cytometry showed that our IL-6-DOTA-rhodamine conjug... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3184868 Tue, 19 Jan 2010 00:00:00 +0100 3184868 http://www.medworm.com/index.php?rid=3184867&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00937.x An effective one-pot synthesis of bis(dihydropyrimidinonoe)benzenes using chlorotrimethylsilane (TMSCl) through Biginelli condensation reaction of terephthalic aldehyde, 1,3-dicarbonyl compounds and (thio)urea or guanidine under microwave irradiation conditions is described. Excellent yields of the products and simple work-up are attractive features of this green protocol. Then, the cytotoxic activities of these compounds were evaluated on five different human cancerous cell lines (Raji, HeLa, LS-180, SKOV-3 and MCF7). Their cytotoxic study indicated that they possessed a weak to moderate activity. Furthermore, the higher activity of compound 4b bearing sulfur in C2 position of pyrimidinone ring showed the importance of this site for cytotoxic activity of these compounds. (Source: Chemical... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3184867 Tue, 19 Jan 2010 00:00:00 +0100 3184867 http://www.medworm.com/index.php?rid=3184866&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00939.x Potent inhibitors of purine nucleoside phosphorylase (PNP) are expected to act as selective agents against T-cell tumours. Five compounds with guanine, three with hypoxanthine, and five with 9-deazaguanine, all connected by a linker with difluoromethylene phosphonic acid, were studied on their inhibitory potential against human and calf PNPs. Antiproliferative activity of these analogues against lymphocytes as well as lymphoma and leukaemia cells has been also investigated. All tested compounds act as multisubstrate analogue inhibitors of PNP with the apparent inhibition constants in the range 5[ndash]100 nm, and also show a slight antiproliferative activity. Analogues with 9-deazaguanine aglycone have better anti-leukaemic and anti-lymphoma activities compared to the guanine and hypoxanth... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3184866 Tue, 19 Jan 2010 00:00:00 +0100 3184866 http://www.medworm.com/index.php?rid=3184865&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00941.x This work describes the synthesis and characterization of three novel complexes derived from N-benzyl-ethylenediamine and oxalate. Precursor compounds were synthesized by reacting N-benzyl-ethylenediamine with K2PtCl4. Subsequent substitution of chlorides by oxalate led to the final products. Elemental analysis and the infrared, 1H, 13C, and 195Pt NMR spectra of these complexes were provided. The cytotoxic activities were investigated against human non-small cell lung carcinoma (A549), mouse non-metastatic cell skin melanoma (B16-F1), mouse metastatic cell skin melanoma (B16-F10), human cell breast adenocarcinoma (MDA-MB-231) and normal cell lines such as baby hamster cell kidney (BHK-21), hamster cell ovary (CHO) and compared to cisplatin and carboplatin under the same experimental condit... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3184865 Tue, 19 Jan 2010 00:00:00 +0100 3184865 http://www.medworm.com/index.php?rid=3184864&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00943.x This study is the first fragment-based crystallographic screen against HIV PR, and the first time that fragments were screened against an inhibitor-bound drug target to search for compounds that both bind to novel sites and stabilize the inhibited conformation of the target. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3184864 Tue, 19 Jan 2010 00:00:00 +0100 3184864 http://www.medworm.com/index.php?rid=3184863&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00944.x G-protein coupled receptors play an essential role in many biological processes. Despite an increase in the number of solved X-ray crystal structures of G-protein coupled receptors, capturing a G-protein coupled receptor in its activated state for structural analysis has proven to be difficult. An unexplored paradigm is stabilization of one or more conformational states of a G-protein coupled receptor via binding a small molecule to the intracellular loops. A short tetrazole peptidomimetic based on the photoactivated state of rhodopsin-bound structure of Gt[alpha](340[ndash]350) was previously designed and shown to stabilize the photoactivated state of rhodopsin, the G-protein coupled receptor involved in vision. A pharmacophore model derived from the designed tetrazole tetrapeptide was us... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3184863 Tue, 19 Jan 2010 00:00:00 +0100 3184863 http://www.medworm.com/index.php?rid=3184862&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00906.x Buxidin (1) and E-Buxenone (2), steroidal alkaloids from Buxus hyrcana, are found to possess potent immunosuppressive properties. The activity was tested in vitro on oxidative burst, chemotaxis, T-cell proliferation, and cytokine production. Both compounds showed a significant immunomodulatory activity with clear suppressive effect on oxidative burst and chemotaxis in a dose-dependent manner. They also exhibited suppressive effect on the phytohemagglutinin-stimulated T-cell proliferation. The immunomodulatory activity was further confirmed by the suppression of IL-2 and IL-4 production. Furthermore, molecular docking studies were performed to investigate the binding mode of Buxidin (1) and E-Buxenone (2) with IL-2. Despite the structural differences between Buxidin (1) and E-Buxenone (2), ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3184862 Tue, 19 Jan 2010 00:00:00 +0100 3184862 http://www.medworm.com/index.php?rid=3184861&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00942.x The design of an unprecedented multicomponent reaction to and synthesis of 2-amino-5-ketoaryl pyrroles are described. The compounds (14 examples) can be synthesized by reacting aminoacetophenone sulfonamides, (hetero)aromatic aldehydes, and malonodinitrile or cyanoacetic acid derivatives in one-pot manner. Pharmacophore features and potential applications of this new scaffold are discussed. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3184861 Tue, 19 Jan 2010 00:00:00 +0100 3184861 http://www.medworm.com/index.php?rid=3099893&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00930.x We report an advanced 'hybrid fingerprint' design concept specifically for the purpose of scaffold hopping. The generation of hybrid fingerprints includes two major steps. In the 'fingerprint reduction' step, bit positions of different types of fingerprints (e.g. substructural and pharmacophore fingerprints) are ranked according to their statistical significance and ability to discriminate between specifically active compounds and database decoys. On the basis of bit ranking, subsets containing the most discriminatory bit positions are determined. In the subsequent 'fingerprint recombination' step, bit subsets from different fingerprints are combined to yield a new compound class-directed fingerprint representation for similarity searching. Here, we generate hybrids from multiple fingerpri... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3099893 Fri, 18 Dec 2009 00:00:00 +0100 3099893 http://www.medworm.com/index.php?rid=3099904&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00919.x In an effort to improve the bioavailability of the non-selective, cyclic enkephalin analogues H-Dmt-c[d-Cys-Gly-Phe-d(or L)-Cys]NH2 (Dmt = 2',6'-dimethyltyrosine), analogues N-methylated at the Phe4 and/or Cys5 residue were synthesized. In comparison with the non-methylated parent peptides, all mono- and N-di-methylated analogues in general retained high binding affinities at all three opioid receptors and high opioid agonist potencies in functional opioid activity assays. The results indicate that the progressive conformational restriction in these compounds upon mono- and di-N-methylation did not significantly affect the in vitro opioid activity profile. A low-energy conformer identified for the conformationally most restricted analogue of the series, H-Dmt-c[D-Cys-Gly-Phe(NMe)-L-Cys(NMe... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3099904 Thu, 17 Dec 2009 00:00:00 +0100 3099904 http://www.medworm.com/index.php?rid=3099903&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00920.x The solid-phase synthesis and full chemical characterization of the medium-length (14-amino acid residues) peptaibol with antibiotic properties of tylopeptin B, originally extracted from the fruiting body of the mushroom Tylopilus neofelleus, are described. These data are accompanied by the results on the solution-phase synthesis via the segment condensation approach of a selected, side-chain protected, analog. A solution conformational analysis, performed by the combined use of FTIR absorption, circular dichroism, and 2D-NMR (the latter technique coupled to molecular dynamics calculations), favors the conclusion that the 3D-structure of tylopeptin B is largely helical with a preference for the [alpha]- or the 310-helix type depending upon the nature of the solvent. Helix topology and (par... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3099903 Thu, 17 Dec 2009 00:00:00 +0100 3099903 http://www.medworm.com/index.php?rid=3099902&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00921.x Binding affinity optimization is critical during drug development. Here, we evaluate the thermodynamic consequences of filling a binding cavity with functionalities of increasing van der Waals radii ([ndash]H, [ndash]F, [ndash]Cl, and CH3) that improve the geometric fit without participating in hydrogen bonding or other specific interactions. We observe a binding affinity increase of two orders of magnitude. There appears to be three phases in the process. The first phase is associated with the formation of stable van der Waals interactions. This phase is characterized by a gain in binding enthalpy and a loss in binding entropy, attributed to a loss of conformational degrees of freedom. For the specific case presented in this article, the enthalpy gain amounts to [minus]1.5 kcal/mol while ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3099902 Thu, 17 Dec 2009 00:00:00 +0100 3099902 http://www.medworm.com/index.php?rid=3099901&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00923.x In this work, a number of lipidic amino alcohols wereas synthesized and evaluated in vitro on cultures of Leishmania amazonensis and Leishmania chagasi. Nine amino alcohols showed inhibition of L. chagasi growth, and seven of them showed inhibition of L. amazonensis with IC50 below 10 [mu]m. Compound 11f was more active than the reference drug amphotericin B against L. chagasi promastigote forms. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3099901 Thu, 17 Dec 2009 00:00:00 +0100 3099901 http://www.medworm.com/index.php?rid=3099900&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00925.x Novel 2-vinyl-8-hydroxyquinoline derivatives as potential antioxidants and regulators of H2O2-induced oxidative stress in rat bone marrow mesenchymal stem cells (MSCs) are first reported. The antiradical properties and the reducing power of these compounds were assessed using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and auto-oxidation of pyrogallol method, respectively. The activity against lipid peroxidation was determined using ammonium thiocyanate method. The results revealed that introduction of electron-donating groups at 2nd position decreased the antioxidant activities of 8-hydroxyquinoline derivatives. In addition, compound 4, the structure of which is similar to melatonin, exhibited superior antioxidant activities in scavenging DPPH free radical, ˙O2 free radical, and anti-LPO... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3099900 Thu, 17 Dec 2009 00:00:00 +0100 3099900 http://www.medworm.com/index.php?rid=3099899&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00926.x Enoyl acyl carrier protein reductase (InhA) is a promising target for the development of antituberculosis drugs. The InhA-bound conformation of an indole-5-amide inhibitor (Genz 10850) (PDB code: IP44) was used to build a pharmacophore model by LigandScout. This model was then successfully used to identify the bioactive conformation and align 40 structurally diverse arylcarboxamide derivatives. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on arylcarboxamides-based InhA inhibitors based on pharmacophore alignment. The best prediction was obtained with CoMSIA model combining steric and electrostatic fields (, r2 = 0.972). The model was validated by an external test set, which gave a good predictive value (). Graphi... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3099899 Thu, 17 Dec 2009 00:00:00 +0100 3099899 http://www.medworm.com/index.php?rid=3099898&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00927.x Antimitotic agents prevent the mitosis process of cell cycle and are generally used for the treatment of cancer with good clinical success. QSAR analysis was performed on 33 reported 2-phenylindole-3-carbaldehyde derivatives to find out the structural requirements of these compounds for higher antimitotic activity. The dataset was divided into test set and training set by k-MCA. Factor analysis-stepwise multiple linear regression (FA-sMLR) method was used to develop statistically significant QSAR equations. QSAR analysis showed importance of topological indices like RTSA indices, structural information content indices, Balaban-type index from van der Waals weighted distance matrix Jhetv, rotatable bond fraction RBF, and Lovasz[ndash]Pelikan index LP1 on biological activity. The study also ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3099898 Thu, 17 Dec 2009 00:00:00 +0100 3099898 http://www.medworm.com/index.php?rid=3099897&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00928.x Neural stem cells have the self-renewal capacity and the ability to differentiate into all types of nerve cells. We previously reported that the tumor necrosis factor receptor-1-derived peptide promotes neural differentiation of fetal rat hippocampal neural stem cells. The tumor necrosis factor receptor-1-derived peptide contains six aromatic amino acid residues among its 14 amino acid residues. To clarify the role of these aromatic amino acid residues in the action of tumor necrosis factor receptor-1-derived peptide on neural stem cells, we synthesized mutant peptides, in which aromatic residues were substituted with alanine, and we assessed their effects. Substitution of the tyrosine residue at position 103 (Y103) or 106 (Y106), the tryptophan residue at position 107 (W107), or the pheny... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3099897 Thu, 17 Dec 2009 00:00:00 +0100 3099897 http://www.medworm.com/index.php?rid=3099896&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00911.x Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukaemia. The second generation BCR/ABL inhibitors nilotinib and dasatinib effectively inhibit most imatinib resistance variants, but are ineffective against the gatekeeper mutant, T315I. Gatekeeper mutation activates the kinase by stabilizing the hydrophobic spine. Here, we describe that the rationally designed compound AP24163 can inhibit native and gatekeeper mutants of the BCR/ABL kinase. Structural modelling suggests that AP24163 affects the flexibility of the P-loop and destabilizes the active conformation by disrupting the hydrophobic spine. In vitro screening for drug resistance identified clones with compound mutations involving both the P-loop and T315I. Our s... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3099896 Thu, 17 Dec 2009 00:00:00 +0100 3099896 http://www.medworm.com/index.php?rid=3099895&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00924.x Ketol-acid reductoisomerase (KARI; EC 1.1.1.86) catalyzes the second common step in branched-chain amino acid biosynthesis. This enzyme is an important target for drug design. Based on the crystal structure of ketol-acid reductoisomerase/N-hydroxy-N-isopropyloxamate (IpOHA) complex, we have carried out high throughput receptor-based virtual screening of the ZINC/drug like database (2 000 000 compounds) to look for novel inhibitors of KARI for the first time. Some novel compounds were found to inhibit rice KARI in vitro among 15 procured compounds. This method can provide useful information for further design and discovery of KARI inhibitors. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3099895 Thu, 17 Dec 2009 00:00:00 +0100 3099895 http://www.medworm.com/index.php?rid=3099894&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00929.x Synthetic collagen model peptides containing carboxylate-modified hydroxyproline residues (PE) have been shown to form a collagen triple helix at low pH (1). Based on the fact that PE-containing peptides unfold on demand by altering the pH, we investigated the folding kinetics of a series of these collagen-based peptides. Refolding data indicated that the introduction of PE residues within a peptide affects the stability and refolding of the collagen peptides through electrostatic interactions and steric hindrance. Moreover, the specific placement of the PE residues within the collagen peptides allowed for selective testing for possible nucleation sites at the termini or the center of the peptides. Specifically, the data demonstrated that collagen peptides may nucleate from either terminal... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3099894 Thu, 17 Dec 2009 00:00:00 +0100 3099894 http://www.medworm.com/index.php?rid=3081994&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00931.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3081994 Sat, 12 Dec 2009 00:00:00 +0100 3081994 http://www.medworm.com/index.php?rid=3039225&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00918.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3039225 Mon, 30 Nov 2009 16:24:38 +0100 3039225 http://www.medworm.com/index.php?rid=3039230&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00912.x This article presents a new metabolomic approach helping to graphically analyse the flexibility of metabolic regulation systems. Its principle consists in extracting a metabolic backbone from iterative combinations of metabolic profiles representing different metabolic trends. The iterated combinations were performed on the basis of Scheffe matrix then averaged to calculate a response matrix of smoothed metabolic profiles. From such a smoothed matrix, a graphical analysis of relationships between metabolites highlighted different scale-dependent variation paths responsible for the observed metabolic trends. Such a flexibility favouring some metabolites at the expense of others was indirectly checked by a single kinetic approach by considering both the variation of maximal concentrations an... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3039230 Mon, 30 Nov 2009 00:00:00 +0100 3039230 http://www.medworm.com/index.php?rid=3039229&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00909.x A series of 1-azolyl-4-phenyl-2-butanones was designed and synthesized for the inhibition of heme oxygenases (heme oxygenase-1 and heme oxygenase-2). The replacement of imidazole by other azoles led to the discovery of novel 1H-1,2,4-triazole- and 1H-tetrazole-based inhibitors equipotent to a lead imidazole-based inhibitor. The inhibitors featuring 2H-tetrazole or 1H-1,2,3-triazole as the pharmacophore were less potent. Monosubstitution at position 2 or 4(5), or identical disubstitution at positions 4 and 5 of imidazole by a variety of electron-withdrawing or electron-donating, small or bulky groups, as well as the replacement of the traditional imidazole pharmacophore by an array of 3- or 5-substituted triazoles, identically 3,5-disubstituted triazoles, 5-substituted-1H- and 5-substituted... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3039229 Mon, 30 Nov 2009 00:00:00 +0100 3039229 http://www.medworm.com/index.php?rid=3039228&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00914.x Photoactive analogs of farnesyl diphosphate (FPP) are useful probes in studies of enzymes that employ this molecule as a substrate. Here, we describe the preparation and properties of two new FPP analogs that contain diazotrifluoropropanoyl photophores linked to geranyl diphosphate via amide or ester linkages. The amide-linked analog (3) was synthesized in 32P-labeled form from geraniol in seven steps. Experiments with Saccharomyces cerevisiae protein farnesyltransferase (ScPFTase) showed that 3 is an alternative substrate for the enzyme. Photolysis experiments with [32P]3 demonstrate that this compound labels the [beta]-subunits of both farnesyltransferase and geranylgeranyltransferase (types 1 and 2). However, the amide-linked probe 3 undergoes a rearrangement to a photochemically unreac... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3039228 Mon, 30 Nov 2009 00:00:00 +0100 3039228 http://www.medworm.com/index.php?rid=3039227&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00913.x Incorporation of amino lactams into biologically active peptides restricts conformational mobility and may enhance selectivity and increase potency. [alpha]- and [beta]-amino [gamma]-lactams (Agl and Bgl), in both S and R configurations, were introduced into the growth hormone secretagogue GHRP-6 using a Fmoc-compatible solid-phase protocol relying on N-alkylation with five- and six-membered cyclic sulfamidates, followed by lactam annulation under microwave heating. Using this protocol in conjunction with IRORI KanTM techniques furnished eleven new GHRP-6 analogs, and their binding affinity IC50 values on both the growth hormone secretagogue receptor 1a (GHS-R1a) and CD36 receptors are herein reported. The results indicate that selectivity towards one receptor or the other can be modulated... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3039227 Mon, 30 Nov 2009 00:00:00 +0100 3039227 http://www.medworm.com/index.php?rid=3039226&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00915.x This study reports replacements to the first residue (d-Arg1) of FM 19, which seek to improve potency by removing the N-terminal amine to eliminate an adverse electrostatic interaction, and alterations to the length of the side chain to eliminate an unfavorable eclipsed conformation observed in the X-ray structure. This study produced two compounds, 1 and 9, with improved [alpha]-thrombin inhibition (IC50 values of 0.66 ± 0.20 [mu]m and 0.57 ± 0.12 [mu]m, respectively). (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3039226 Mon, 30 Nov 2009 00:00:00 +0100 3039226 http://www.medworm.com/index.php?rid=3014978&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00917.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3014978 Sat, 21 Nov 2009 00:00:00 +0100 3014978 http://www.medworm.com/index.php?rid=3014979&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00916.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=3014979 Fri, 20 Nov 2009 00:00:00 +0100 3014979 http://www.medworm.com/index.php?rid=2966562&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00908.x Plasmodium falciparum dihydrofolate reductase (Pf DHFR) enzyme is one of the validated targets in the treatment of malaria using typical antifolates such as cycloguanil and pyrimethamine. However, point mutations at amino acid residues such as Ala16, Ile51, Cys59, Ser108 and Ile164 in the active site of the wild-type enzyme resulted in a widespread resistance of the parasite to these drugs. Thus, design and discovery of new potential Pf DHFR inhibitors, equally active against both the wild-type and mutant strains, is an urgent need. Catalyst software was used to generate a 3D pharmacophore query based on the bioactive conformation of WR99210 extracted from the X-ray crystal structure of quadruple mutant PfDHFR enzyme. Validation criteria based on the experimentally determined conformation ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2966562 Fri, 06 Nov 2009 00:00:00 +0100 2966562 http://www.medworm.com/index.php?rid=2966563&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00905.x Bcr-Abl is the oncogenic protein tyrosine kinase responsible for chronic myeloid leukemia (CML). Treatment of the disease with imatinib (Gleevec) often results in drug resistance via kinase mutations at the advanced phases of the disease, which has necessitated the development of new mutation-resistant inhibitors, notably against the T315I gatekeeper mutation. As part of our efforts to discover such mutation resistant Abl inhibitors, we have focused on optimizing purine template kinase inhibitors, leading to the discovery of potent DFG-in and DFG-out series of Abl inhibitors that are also potent Src inhibitors. Here we present crystal structures of Abl bound by two such inhibitors, based on a common N9-arenyl purine, and that represent both DFG-in and -out binding modes. In each structure ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2966563 Thu, 05 Nov 2009 00:00:00 +0100 2966563 http://www.medworm.com/index.php?rid=2962604&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00910.x Aminoalkylindoles (AAIs), although structurally dissimilar from the classical cannabinoids, are known to be capable of binding to cannabinoid receptors and of evoking cannabinomimetic responses. With the aim of investigating the structure[ndash]activity relationships (SAR) for the binding of non-classical agonists to CB1 and CB2 cannabinoid receptors, we designed and synthesized a series of indole derivatives. The compounds were tested for their analgesic action by formalin test and compared to WIN 55212-2, an AAI acting to the cannabinoid receptors. In receptor binding assay, compound 5 showed affinity for the CB1 receptor comparable to WIN 55212-2. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2962604 Thu, 05 Nov 2009 00:00:00 +0100 2962604 http://www.medworm.com/index.php?rid=2962606&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00907.x The three-dimensional X-ray crystal structure of carboxypeptidase A, a zinc-dependent hydrolase, covalently modified by a mechanism-based thiirane inactivator, 2-benzyl-3,4-epithiobutanoic acid, has been solved to 1.38 Å resolution. The interaction of the thiirane moiety of the inhibitor with the active site zinc ion promotes its covalent modification of Glu-270 with the attendant opening of the thiirane ring. The crystal structure determination at high resolution allowed for the clear visualization of the covalent ester bond to the glutamate side chain. The newly generated thiol from the inhibitor binds to the catalytic zinc ion in a monodentate manner, inducing a change in the zinc ion geometry and coordination, while its benzyl group fits into the S1' specificity pocket of the enzyme. ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2962606 Wed, 04 Nov 2009 00:00:00 +0100 2962606 http://www.medworm.com/index.php?rid=2938583&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00904.x In this study, we developed a prototype antimicrobial peptide capable of achieving high activity exclusively at low environmental pH to target bacterial species like Streptococcus mutans that produce acid and thrive under the low pH conditions detrimental for tooth integrity. The features of clavanin A, a naturally occurring peptide rich in histidine and phenylalanine residues with pH-dependent antimicrobial activity, served as a design basis for these prototype 'acid-activated peptides' (AAPs). Employing the major cariogenic species S. mutans as a model system, the two AAPs characterized in this study exhibited a striking pH-dependent antimicrobial activity, which correlated well with the calculated charge distribution. This type of peptide represents a potential new way to combat dental ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2938583 Thu, 29 Oct 2009 00:00:00 +0100 2938583 http://www.medworm.com/index.php?rid=2938584&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00899.x In this study, we review important progress in drug metabolism and common in silico techniques adopted to predict drug regioselectivity, stereoselectivity, reactive metabolites, induction, inhibition and mechanism-based inactivation, as well as their implementation in hit-to-lead drug discovery. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2938584 Wed, 28 Oct 2009 00:00:00 +0100 2938584 http://www.medworm.com/index.php?rid=2911780&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00901.x Resveratrol is a plant polyphenol capable of exerting beneficial metabolic effects which are thought to be mediated in large by the activation of the NAD+-dependent protein deacetylase SIRT1. Although resveratrol has been claimed to be a bona fide SIRT1 activator using a peptide substrate (Fluor de Lys-SIRT1 peptide substrate), recent reports indicate that this finding might be an experimental artifact and need to be clarified. Here, we show that: (i) the Fluor de Lys-SIRT1 peptide is an artificial SIRT1 substrate because in the absence of the covalently linked fluorophore the peptide itself is not a substrate of the enzyme, (ii) resveratrol does not activate SIRT1 in vitro in the presence of either a p53-derived peptide substrate or acetylated PGC-1[alpha] isolated from cells, and (iii) a... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2911780 Tue, 20 Oct 2009 23:00:00 +0100 2911780 http://www.medworm.com/index.php?rid=2911784&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00884.x The design, synthesis and utility of fluorescence probes that bind to the DFG-out conformation of p38[alpha] kinase are described. Probes that demonstrate good affinity for p38[alpha], have been identified and one of the probes, PF-04438255, has been successfully used in an high throughput screening (HTS) assay to identify two novel non-classical p38[alpha] inhibitors. In addition, a cascade activity assay was utilized to validate the selective binding of these non-classical kinase inhibitors to the unactive form of the enzyme. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2911784 Mon, 19 Oct 2009 23:00:00 +0100 2911784 http://www.medworm.com/index.php?rid=2911783&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00892.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2911783 Mon, 19 Oct 2009 23:00:00 +0100 2911783 http://www.medworm.com/index.php?rid=2911782&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00893.x P-selectin is a promising target for developing novel atherosclerosis drugs. To understand the structure[ndash]activity correlation of quinolines-based P-selectin inhibitors, we have carried out a combined molecular docking and three-dimensional quantitative structure[ndash]activity relationship (3D-QSAR) modeling study. The study has resulted in two types of satisfactory 3D-QSAR models, including the CoMFA model (r2, 0.863; q2, 0.589) and CoMSIA model (r2, 0.866; q2, 0.636), to predict the biological activity of new compounds. The detailed microscopic structures of P-selectin binding with inhibitors have been studied by molecular docking. We have also developed docking based 3D-QSAR models (CoMFA with r2, 0.934; q2, 0.591; CoMSIA with r2, 0.896; q2, 0.573). The contour maps obtained from ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2911782 Mon, 19 Oct 2009 23:00:00 +0100 2911782 http://www.medworm.com/index.php?rid=2911781&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00896.x A hybrid quantum mechanics/molecular mechanics scheme is described to explore the structural basis and energetic behavior of short peptide segments binding to HLA-A*0201. This method was used to analyze 50 structurally diverse non-americ peptides and results showed that the quantum mechanics/molecular mechanics-derived interaction energy, in conjugation with empirical desolvation free energy, linearly correlate well with the experimentally determined affinity. Further systematic investigations of several HLA-A*0201[ndash]peptide complexes confirmed the importance of anchor residues and water molecules in peptide binding, and quantitatively showed that: (i) the primary and second anchor residues provide a larger binding energy contribution (>3 kcal/mol) than the non-anchor residues (4 kcal/... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2911781 Mon, 19 Oct 2009 23:00:00 +0100 2911781 http://www.medworm.com/index.php?rid=2898142&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00891.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2898142 Thu, 15 Oct 2009 23:00:00 +0100 2898142 http://www.medworm.com/index.php?rid=2898144&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00897.x This study will facilitate the rational design of more potent Physostigmine compounds which might have better activity and reduce toxicity for the treatment of Alzheimer disease. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2898144 Wed, 14 Oct 2009 23:00:00 +0100 2898144 http://www.medworm.com/index.php?rid=2898143&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00903.x A computational application to predict, probe and interpret the activities of a series of congeneric compounds inhibiting extracellular signal-regulated kinase 2 protein kinase is presented. The study shows that molecular dynamics coupled with molecular mechanics Poisson[ndash]Boltzmann solvent accessible surface area free energy estimation is a suitable tool for investigating the experimental binding activities of ligands to protein kinases. Computed and experimental binding activities were found to be significantly correlated. Moreover, the interpretation of the X-ray co-crystal structure in conjunction with computational results shows that the hinge region of the protein insure the principal binding site via multiple hydrogen bonding interactions, whereas fine-modulation of biological a... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2898143 Wed, 14 Oct 2009 23:00:00 +0100 2898143 http://www.medworm.com/index.php?rid=2885819&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00902.x A series of sulfonamides incorporating sugar moieties and the sulfanilamide scaffold have been investigated for their interaction with the secretory isoform of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), CA VI. This isoform is secreted in saliva, tears, and milk of mammals [ndash] where it plays important physiological roles [ndash] even if little is understood at this moment regarding its inhibition, due to the lack of potent and/or selective inhibitors. Here we report a series of low nanomolar and subnanomolar CA VI inhibitors, belonging to the glycosylamine[ndash]sulfanilamide class. The glucose, ribose, arabinose, xylose, and fucose derivatives showed excellent CA VI inhibitory activity, with Kis in the range of 0.56[ndash]5.1 nm, whereas the least active derivatives, incorpor... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2885819 Mon, 12 Oct 2009 23:00:00 +0100 2885819 http://www.medworm.com/index.php?rid=2885822&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00894.x This study is an attempt to transform this data into useful knowledge which can be directly used to design more effective protein tyrosine phosphatase inhibitors. In this study, we have built quantitative models for activity of co-crystallized protein tyrosine phosphatase inhibitors using two new approaches developed in our group, i.e. receptor[ndash]ligand interaction and Structure-based compound optimization, prioritization and evolution based on receptor[ndash]ligand interaction descriptors and residue-wise interaction energies as descriptors, respectively. These models have given insights into the receptor[ndash]ligand interactions essential for modulating the activity of PTP1B inhibitors. An external validation set of 22 molecules was used to test predictive power of these models on e... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2885822 Sun, 11 Oct 2009 23:00:00 +0100 2885822 http://www.medworm.com/index.php?rid=2885821&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00898.x We describe herein the synthesis and evaluation of these structural variants as potent inhibitors of gelatinases. Two (compounds 5b and 5d) among the four synthetic stereoisomers were found to exhibit slow-binding inhibition of gelatinases and MMP-14 (MT1-MMP), which is a hallmark of the mechanism of this class of inhibitors. The ability of these compounds to inhibit MMP-2, MMP-9, and MMP-14 could target cancer tissues more effectively. Metabolism of the newly synthesized inhibitors showed that both oxidation at the [alpha]-position to the sulfonyl group and oxidation at the para position of the terminal phenyl ring were prevented. Instead oxidation on the thiirane sulfur is the only biotransformation pathway observed for these gelatinase inhibitors. (Source: Chemical Biology and Drug Desi... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2885821 Sun, 11 Oct 2009 23:00:00 +0100 2885821 http://www.medworm.com/index.php?rid=2885820&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00900.x Androstene steroids are metabolites of dehydroepiandrosterone and exist as androstene-diols or -triols in [alpha]- and [beta]-epimeric forms based upon the placement of the hydroxyl groups relative to the plane of the [Delta]5cycloperhydrophenanthrene ring. 5-Androstene-3[beta],17[beta]-diol (3[beta],17[beta]-AED) functions to upregulate immunity and the addition of a third hydroxyl group at C-7 in the [alpha]- or [beta]-orientation (3[beta],7[alpha],17[beta]-AET and 3[beta],7[beta],17[beta]-AET, respectively) enhances the immunological activity of the molecule. In contrast, 5-androstene-3[beta],17[alpha]-diol (3[beta],17[alpha]-AED) possesses potent anti-tumor activity. We synthesized a new androstene by adding a third hydroxyl group at C-7 to make 5-androstene-3[beta],7[alpha],17[alpha]-... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2885820 Sun, 11 Oct 2009 23:00:00 +0100 2885820 http://www.medworm.com/index.php?rid=2868483&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00881.x (±)-2-[(4-Phenoxyphenylsulfonyl)methyl]thiirane 1 is a potent and selective mechanism-based inhibitor of the gelatinase sub-class of the zinc-dependent matrix metalloproteinase family. Inhibitor 1 has excellent activity in in vivo models of gelatinase-dependent disease. We demonstrate that the mechanism of inhibition is a rate-limiting gelatinase-catalyzed thiolate generation via deprotonation adjacent to the thiirane, with concomitant thiirane opening. A corollary to this mechanism is the prediction that thiol-containing structures, related to thiirane-opened 1, will possess potent matrix metalloproteinase inhibitory activity. This prediction was validated by the synthesis of the product of this enzyme-catalyzed reaction on 1, which exhibited a remarkable Ki of 530 pm against matrix meta... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2868483 Tue, 06 Oct 2009 23:00:00 +0100 2868483 http://www.medworm.com/index.php?rid=2857183&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00883.x The cellular fingerprint, a novel in silico screening approach, was developed to identify new biologically active compounds in combination with structural fingerprints. To this end, high-throughput screening (HTS) data from the National Cancer Institute have been used. To validate this method, we have selected the proapoptotic, natural compound betulinic acid (BA). Because of its antiproliferative effect on a variety of cancer cell lines, the identification of novel BA analogs is of great interest. Novel analogs have been identified and validated in different apoptosis assays. In addition, the novel approach exhibited a strong correlation between structural similarity and biological activity, so that it offers enormous potential for the identification of novel biologically active compounds... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2857183 Fri, 02 Oct 2009 23:00:00 +0100 2857183 http://www.medworm.com/index.php?rid=2841965&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00890.x We introduce a computational scaling methodology that utilizes protein[ndash]ligand interaction information extracted from complex crystal structures to enrich similarity searching using structural fingerprints with compound class-specific information. Scaling factors are derived to emphasize fingerprint bit positions that result from interacting fragments of bound ligands and correspond to frequently occurring structural features. Through interaction-based scaling, this information is transferred to standard fingerprints of multiple reference compounds. In systematic search calculations, fingerprints scaled on the basis of three-dimensional information are found to produce higher recall rates of active compounds than alternative types of scaled and non-scaled fingerprints. (Source: Chemic... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2841965 Mon, 28 Sep 2009 23:00:00 +0100 2841965 http://www.medworm.com/index.php?rid=2841970&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00880.x High throughput screening and other techniques commonly used to identify lead candidates for drug development usually yield compounds with binding affinities to their intended targets in the mid-micromolar range. The affinity of these molecules needs to be improved by several orders of magnitude before they become viable drug candidates. Traditionally, this task has been accomplished by establishing structure activity relationships to guide chemical modifications and improve the binding affinity of the compounds. As the binding affinity is a function of two quantities, the binding enthalpy and the binding entropy, it is evident that a more efficient optimization would be accomplished if both quantities were considered and improved simultaneously. Here, an optimization algorithm based upon ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2841970 Sun, 27 Sep 2009 23:00:00 +0100 2841970 http://www.medworm.com/index.php?rid=2841969&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00882.x Brevinin-2 related peptide (B2RP; GIWDTIKSMG10KVFAGKILQN20L.NH2), first isolated from skin secretions of the mink frog Lithobates septentrionalis, shows broad-spectrum antimicrobial activity but its therapeutic potential is limited by moderate hemolytic activity. The peptide adopts an [alpha]-helical conformation in a membrane-mimetic solvent but amphipathicity is low. Increasing amphipathicity together with hydrophobicity by the substitutions Lys16[rarr]Leu and Lys16[rarr]Ala increased hemolytic activity approximately fivefold without increasing antimicrobial potency. The substitution Leu18[rarr]Lys increased both cationicity and amphipathicity but produced decreases in both antimicrobial potency and hemolytic activity. In contrast, increasing cationicity of B2RP without changing amphipat... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2841969 Sun, 27 Sep 2009 23:00:00 +0100 2841969 http://www.medworm.com/index.php?rid=2841968&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00885.x Polyphenolic natural products from green tea and red wine have been identified as metalloproteinase inhibitors. Members from the flavonoid and stilbene families found to possess metalloproteinase inhibitory activities include ([minus])-epigallocatechin gallate, ([minus])-epicatechin gallate and piceatannol, but their minimally active pharmacophores have not been evaluated. The present study has examined compounds that are structural components of or structurally related to ([minus])-epigallocatechin gallate, ([minus])-epicatechin gallate and piceatannol for inhibition of aggrecanases and four representative matrix metalloproteinases. Piceatannol and pyrogallol were found to inhibit all aggrecanases and matrix metalloproteinases studied, indicating a crucial reliance on multiple hydroxyl gr... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2841968 Sun, 27 Sep 2009 23:00:00 +0100 2841968 http://www.medworm.com/index.php?rid=2841967&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00887.x The diastereoselectivity of the intermolecular 1,3-dipolar cycloaddition reaction of d-glucose-derived nitrones with both cyclic and acyclic dipolarophiles were studied. The reaction of nitrone with acyclic dipolarophiles resulted in the formation of the endo adduct exclusively whereas with cyclic dipolarophiles endo adduct was obtained as the major product. Antibacterial activity was evaluated for these eighteen isoxazolidine derivatives against Staphylococcus aureus NCIM5021, Escherichia coli NCIM 2931 and Pseudomonas aeruginosa NCIM 5029 by twofold dilution technique using resazurin as the indicator dye. Quantitative structureactivity relationships were developed with fourteen and the model was validated with four data. Electronic and spatial descriptors were the major contributors in a... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2841967 Sun, 27 Sep 2009 23:00:00 +0100 2841967 http://www.medworm.com/index.php?rid=2841966&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00888.x We have developed quantitative structure[ndash]activity relationship models for a series of hetero aromatic tetrahydro-1,4-oxazine derivatives exhibiting antioxidant as well as squalene synthase inhibitory activities using genetic function approximation and genetic partial least squares regression techniques. The independent variables used for the model development include descriptors belonging to various categories, viz. molecular shape analysis descriptors, Jurs spatial descriptors, shadow indices, electronic parameters and quantum chemical descriptors (Mulliken charges of the common atoms shared by the 22 oxazine derivatives). The developed models were validated internally by leave-one-out and leave-many (1/7th)-out cross-validation techniques. The two pairs of models developed for the ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2841966 Sun, 27 Sep 2009 23:00:00 +0100 2841966 http://www.medworm.com/index.php?rid=2823475&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00886.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2823475 Tue, 22 Sep 2009 23:00:00 +0100 2823475 http://www.medworm.com/index.php?rid=2818939&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00870.x Serine proteases are a very large class of enzymes, many of which represent important targets for therapeutic agents against a wide variety of disease states. The similarity in active site architecture for these proteases has often allowed inhibitor design strategies for a particular target to be successfully applied to other enzymes in the class. In many cases, the presence of a bulky P3 amino acid residue in peptide-based inhibitors is central to conferring an extended peptide conformation, critical to binding of the ligands to serine protease active sites. The dimethylthiazolidine carboxylic acid 'residue' was found to be effective as a novel P3 replacement in peptidomimetic inhibitors of two distinct serine proteases, the hepatitis C NS3 protease and the human cytomegalovirus maturatio... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2818939 Mon, 21 Sep 2009 23:00:00 +0100 2818939 http://www.medworm.com/index.php?rid=2781407&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00878.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2781407 Tue, 08 Sep 2009 23:00:00 +0100 2781407 http://www.medworm.com/index.php?rid=2781406&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00873.x A strategy for developing accurate quantitative structure[ndash]activity relationship models enabling predictions of biological properties, when suitable knowledge concerning both ligands and biological target is available, was tested on a data set where molecules are characterized by high structural diversity. Such a strategy was applied to human ether-a-go-go-related gene K+ channel inhibition and consists of a combination of ligand- and structure-based approaches, which can be carried out whenever the three-dimensional structure of the target macromolecule is known or may be modeled with good accuracy. Molecular conformations of ligands were obtained by means of molecular docking, performed in a previously built theoretical model of the channel pore, so that descriptors depending upon t... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2781406 Tue, 08 Sep 2009 23:00:00 +0100 2781406 http://www.medworm.com/index.php?rid=2781405&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00879.x [beta]-Lactam antibiotics are among the most important drugs used to fight bacterial infection. Overuse and misuse of [beta]-lactam antibiotics has caused the evolution of resistance mechanisms, allowing pathogenic bacteria to survive antibiotic treatment. The major source of resistance to [beta]-lactam antibiotics occurs through production of enzymes called [beta]-lactamases capable of catalyzing hydrolysis of the [beta]-lactam rings in these drug compounds. The metallo-[beta]-lactamases have become a major threat due to their broad substrate specificities; there are no clinically useful inhibitors for these metalloenzymes. We have obtained single-stranded DNA's that are potent inhibitors of the Bacillus cereus 5/B/6 metallo-[beta]-lactamase. These are rapid, reversible, non-competitive i... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2781405 Tue, 08 Sep 2009 23:00:00 +0100 2781405 http://www.medworm.com/index.php?rid=2719226&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00869.x The molecular chaperone DnaK is essential for the survival of bacterial pathogens in the hostile environment of the host. Hence, it is in principle a promising target for drug design but for which no current inhibitors are available apart from certain antimicrobial peptides. To this end, we have screened libraries of small molecules for their ability to interact with the substrate-binding domain of DnaK. The most promising hit from the screen was synthesized and along with its analogs subjected to further assays to determine their binding affinity and ability to interfere with bacterial growth. This work resulted in the identification of a number of compounds that bind with submicromolar affinity and capable of inhibiting Yersinia pseudotuberculosis growth more effectively than the previou... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2719226 Thu, 20 Aug 2009 23:00:00 +0100 2719226 http://www.medworm.com/index.php?rid=2719227&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00867.x The opioid peptide H-Tyr-c[D-Cys-Phe-Phe-Cys]NH2 cyclized via a methylene dithiother is a potent and selective [mu] opioid agonist (Przydial M.J. et al., J Peptide Res, 66, 2005, 255). Dicarba analogues of this peptide with Tyr, 2'6'-dimethyltyrosine (Dmt), 3-[2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp] in the 1-position were prepared. The peptides were synthesized on solid-phase by substituting d-allylglycine and (2S)-2-amino-5-hexenoic acid in position 2 and 5, respectively, followed by ring-closing metathesis. Mixtures of cis and trans isomers of the resulting olefinic peptides were obtained, and catalytic hydrogenation yielded the saturated [ndash]CH2[ndash]CH2[ndash] bridged peptides. All six Tyr1- and Dm... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2719227 Wed, 19 Aug 2009 23:00:00 +0100 2719227 http://www.medworm.com/index.php?rid=2715500&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00876.x A series of N-benzyl-indole-3-imine-, amine derivatives and their 5-bromo congeners were synthesized and their biological activity were evaluated against the pp60c-Src tyrosine kinase target. To afford the imine derivatives, aldehydes were reacted with substituted benzylamines and the corresponding amine derivatives were obtained by NaBH4 reduction of these imines. Except insoluble N-benzyl-indole-3-imine derivatives, all the derivatives showed some activity against the kinase target. Screening of these compounds for their biological activity revealed that among N-benzyl-indole derivatives, those bearing 5-bromo substitution have the enhanced potency, where the amine derivatives were more active than imines. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2715500 Wed, 19 Aug 2009 23:00:00 +0100 2715500 http://www.medworm.com/index.php?rid=2715505&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00874.x In this study, we continued to study antiherpetic properties of acyclovir 5'-hydrogenphosphonate (Hp-ACV) in cell cultures and animal models. Hp-ACV was shown to inhibit the development of herpetic infection in mice induced by the HSV-1/L2 strain. The compound suppressed replication of both ACV-sensitive HSV-1/L2 and ACV-resistant HSV-1/L2/R strains in Vero cell culture. Viral population resistant to Hp-ACV (HSV-1/L2/RHp-ACV) was developed much slower than ACV-resistant population. The analysis of Hp-ACV-resistant clones isolated from the HSV-1/L2/RHp-ACV population demonstrated their partial cross-resistance to ACV. The mutations determining the resistance of HSV-1 clones to Hp-ACV were partly overlapped with mutations defining ACV resistance but did not always coincide. HSV-1/L2/RHp-ACV ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2715505 Tue, 18 Aug 2009 23:00:00 +0100 2715505 http://www.medworm.com/index.php?rid=2715504&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00877.x This study aimed to evaluate the 4-(6'-thiopurine)-7-chloroquinoline, a novel quinoline/6-thiopurine conjugate, for the treatment of Gallus gallus experimentally infected with Plasmodium juxtanucleare, an avian malaria agent. The avian group treated with 4-(6'-thiopurine)-7-chloroquinoline showed a significative parasite clearance and maintained a low level of parasitaemia, when compared with the untreated control group and to the chloroquine treated avian group. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2715504 Tue, 18 Aug 2009 23:00:00 +0100 2715504 http://www.medworm.com/index.php?rid=2715503&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00871.x The human immunodeficiency viruses type 1 reverse transcriptase is a major target for drug development. Inhibition of this enzyme has been one of the primary therapeutic strategies in suppressing the replication of human immunodeficiency viruses type 1. A series of 2-amino-6-arylsulfonylbenzonitrile derivatives was subjected to quantitative structure[ndash]activity relationship analysis. The newly proposed substituent electronic descriptors were investigated for quantitative structure[ndash]activity relationship modeling of the compounds and a comparison was made with the conventional molecular descriptors. Two chemometrics methods including multiple linear regressions and partial least squares combined with genetic algorithm for variable selection were employed to make connections between... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2715503 Tue, 18 Aug 2009 23:00:00 +0100 2715503 http://www.medworm.com/index.php?rid=2715502&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00849.x Mono- and bis-indolomorphinans were synthesized through a multi-step synthetic approach from the alkaloid, thebaine, to further explore the C-ring SAR (structure-activity relationship) of morphinan scaffold. Both mono-indoles displayed good binding affinity and selectivity for the [delta] receptor, with compound 6b possessed the highest Ki value of 1.45 nm at this receptor. Bisindolomorphinans 7a,b did not have appreciable affinity for both [delta] and [kappa] receptors, but moderate binding at the [mu] receptor was observed. Functional assays indicated that the newly synthesized mono-indole 6b was [delta]-agonist, opposite to the [delta]-antagonist profile of naltrindole. Bisindoles 7a,b were [mu]-agonists. This work further confirms that the phenol component in opioids is essential for h... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2715502 Tue, 18 Aug 2009 23:00:00 +0100 2715502 http://www.medworm.com/index.php?rid=2715501&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00875.x In this study, we have determined the effect of [mu]-opioid receptor agonists and antagonists on the urokinase plasminogen activator secretion in MCF-7 cell line. It was shown that [mu]-opioid receptor agonists, such as morphine and endomorphins, greatly stimulate urokinase plasminogen activator secretion, while naloxone and MOR-selective antagonists elicit the opposite effect. The same tendency was observed also on the urokinase plasminogen activator mRNA level. However, neither agonists nor antagonists had any effect on proliferation of MCF-7 cells. The findings reported in this study may be useful in designing further experiments aimed at elucidating the role of the opioid system in cancer cells. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2715501 Tue, 18 Aug 2009 23:00:00 +0100 2715501 http://www.medworm.com/index.php?rid=2711638&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00872.x Anxiety disorders, caused by continuous or acute stress or fear, have been highly prevailing psychiatric disorders. For the acute treatment of the disorders, benzodiazepines have been widely used despite having liabilities that limit their utility. Alternatively, endogenous nociceptin/orphanin FQ and nociceptin/orphanin FQ peptide receptor (or opioid-receptor-like-1 receptor) have important roles in the integration of emotional components, e.g. anxiolytic activity is the key behavioral action of nociceptin/orphanin FQ in brain. In our preceding study, various structurally novel 1,2-disubstituted benzimidazole derivatives were designed and synthesized as highly potent nociceptin/orphanin FQ peptide receptor selective full agonists in vitro with high or moderate nociceptin/orphanin FQ peptid... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2711638 Tue, 18 Aug 2009 23:00:00 +0100 2711638 http://www.medworm.com/index.php?rid=2711639&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00866.x The natural product ([minus])-pironetin is a structurally simple small molecule microtubule-perturbing agent whose biological activities appear to be exquisitely dependent on defined stereochemistry and the presence of an eletrophilic [alpha],[beta]-unsaturated lactone moiety. We used alkaloid-catalyzed acyl halide-aldehyde cyclocondensation reactions in asymmetric total syntheses of ([minus])-pironetin and three synthetic analogs, and evaluated their biological activities by high-content analysis in cell culture and in a zebrafish model. Synthetic ([minus])-pironetin and 2,3-dihydro-3-hydroxypironetin caused mitotic arrest and programmed cell death in human lung cancer cells but not in normal lung fibroblasts, had nanomolar growth inhibitory activity in multi-drug resistant cells, and inh... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2711639 Mon, 17 Aug 2009 23:00:00 +0100 2711639 http://www.medworm.com/index.php?rid=2708416&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00865.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708416 Sun, 16 Aug 2009 23:00:00 +0100 2708416 http://www.medworm.com/index.php?rid=2708415&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00860.x This study demonstrated the potential lead of the diamino-triazaspirodienes in anticancer chemotherapeutical agents' discovery. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708415 Sun, 16 Aug 2009 23:00:00 +0100 2708415 http://www.medworm.com/index.php?rid=2708414&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00857.x Zonisamide, sulthiame, and topiramate, clinically used antiepileptics are inhibitors of mammalian carbonic anhydrase isoforms I[ndash]XIV, indiscriminately inhibiting with variable efficacy all the catalytically active isoforms present in mammals. However, it is not clear which carbonic anhydrase isozymes might be responsible for the anticonvulsant activity of such sulfonamide/sulfamate drugs. We examine here the full inhibition profile against all mammalian carbonic anhydrases of the above antiepileptic drugs together with two investigational, structurally related sulfonamides, one of which is and the other is not an anticonvulsant. No clear-cut data allow us to propose which are the carbonic anhydrases involved in these processes, but strong carbonic anhydrase II, VII, IX, and XII inhibi... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708414 Sun, 16 Aug 2009 23:00:00 +0100 2708414 http://www.medworm.com/index.php?rid=2708413&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00863.x With cancer-related fatalities being the second leading cause of death in the USA, understanding the activity of effective chemotherapeutic agents is critical to addressing prostate and other cancers. Celecoxib, an FDA-approved drug for the treatment of colon tumors, has been used successfully as a lead compound in the development of antiproliferative agents. The ability of celecoxib to inhibit the development and progression of tumors has been connected to a number of mechanisms of actions that are both dependent on and independent of its cyclooxygenase-2 activity. A structure-based approach has been employed to develop a model that underscores the structural significance of celecoxib as an antiproliferative agent. By evaluating the structure activity of this library of molecules, we were... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708413 Sun, 16 Aug 2009 23:00:00 +0100 2708413 http://www.medworm.com/index.php?rid=2708412&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00854.x We herein provide a new and rapid protocol to generate derivatives of seleno amino acid, including methyl selenocysteine, selenomethionine, and selenocystine. Applying the isocyanide-based multicomponent reaction Ugi-4C-5C reaction, we show that each of the commercially available seleno amino acids are good substrate for these reactions and can be used together with complementary oxocomponents and isocyanides to generate highly diverse functionalized selenium-containing compounds. These compounds might become useful tools for applications in chemical biology to elucidate the role of selenium in biochemistry. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708412 Sun, 16 Aug 2009 23:00:00 +0100 2708412 http://www.medworm.com/index.php?rid=2708411&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00850.x A series of disubstituted 4(3H) quinazolines were designed for potential application in tumors. Firstly, N-benzoyl anthranilic acid is formed, which undergoes cyclization in the presence of pyridine. Subsequently, nucleophilic attack by semicarbazide on the carbonyl carbon gives 2-substituted 3-carbamido 4(3H) quinazolones, which gives final compound with appropriate substitution. The final as well as intermediate products were confirmed by NMR, FT-IR, and mass spectrometry. In vitro toxicity was performed with different cell lines and showed that the connection of hydrophilic styryl to quinazoline moiety increases its efficacy. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708411 Sun, 16 Aug 2009 23:00:00 +0100 2708411 http://www.medworm.com/index.php?rid=2708410&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00861.x A theoretical study on binding orientations and quantitative structure[ndash]activity relationship of thiophene derivatives as inhibitors towards tubulin has been carried out by using the docking analysis and the comparative molecular field analysis. The appropriate binding orientations and conformations of these compounds interacting with tubulin were revealed by docking study; and a 3D-quantitative structure[ndash]activity relationship model showing significant statistical quality and satisfying predictive ability was established, in which the correlation coefficient (R2) and cross-validation coefficient (q2) are 0.949 and 0.743, respectively. The same model was further applied to predict the pIC50 values for nine congeneric compounds as external test set, and the predictive correlation ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708410 Sun, 16 Aug 2009 23:00:00 +0100 2708410 http://www.medworm.com/index.php?rid=2708409&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00858.x The encouraging results of preliminary toxicological studies on imidazolium-based ionic liquids provide good opportunities for the development of ionic liquids in biomedical applications. In this work, the polymerized ionic liquid poly[3-butyl-1-vinylimidazolium L-proline salt] has been synthesized as a gene vector. The interaction of poly[3-butyl-1-vinylimidazolium L-proline salt] with DNA was studied by agarose gel electrophoresis. The cell viability was determined through PI (propidium iodine) staining and flow cytometry, showing marginal toxicity toward the cells examined. The transfection efficiency was evaluated through the in vitro transfection experiment. The results indicated that the imidazolium cation had a high binding ability to DNA, and the condensed DNA in the complexes coul... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708409 Sun, 16 Aug 2009 23:00:00 +0100 2708409 http://www.medworm.com/index.php?rid=2708408&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00859.x A series of oxazolidinone derivatives with [alpha]-substituted acetylpiperazinyl groups were prepared. Their in vitro antibacterial activities were studied against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis. The compounds with chloroacetyl-piperazinyl or dichloroacetyl-piperazinyl group were found to have superior antibacterial activities to linezolid against most of tested Gram-positive pathogens. The compounds with propionylpiperaziny or fluoroacetylpiperazinyl group were found to have comparable antibacterial activities with linezolid. However, the replacement of phenyl ring of the compounds with pyridine ring resulted in the significant loss of antibacterial activity. (Sourc... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708408 Sun, 16 Aug 2009 23:00:00 +0100 2708408 http://www.medworm.com/index.php?rid=2708407&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00864.x A series of aryl-acetic acids and hydroxamic acids possessing antioxidant/anti-inflammatory activities were tested for anticancer activity using different cancer cell lines. The compounds have low antitumor activity considering the 1/IC50 values attained for the cell lines. Compound 5iv presents the best anticancer activity. Moreover, they depict the same activity pattern, suggesting similar mechanisms of action correlated to their antioxidant activities. The obtained results subjected in a QSAR analysis. It seems reasonable to conclude that the same molecular structural features are responsible for the compounds biological activity, these being the electron accepting/donating ability and the molar volume. For all cellular lines (HT-29, A-549 and OAW-42) log 1/IC50 exhibits a reasonable co... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708407 Sun, 16 Aug 2009 23:00:00 +0100 2708407 http://www.medworm.com/index.php?rid=2708406&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00852.x Reverse transcriptase, being the pivot in human immunodeficiency virus replication, is one of the most attractive targets for the development of new antiretroviral agents. We applied a virtual screening workflow based on a combination of physicochemical filters with high-throughput rigid molecular docking to discover novel efficient lead scaffolds for human immunodeficiency virus type 1 reverse transcriptase inhibition. In our protocol, different filters were employed to enrich the lead-likeness and improve the ligands efficiency of the filtered compounds. Out of the 238 819 compounds included in the Natinal Cancer Institute database, 500 virtual screening hits were retrieved employing filter and fred (molecular docking engine) softwares. Four compounds from the 20 highest ranking scored h... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708406 Sun, 16 Aug 2009 23:00:00 +0100 2708406 http://www.medworm.com/index.php?rid=2708405&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00855.x Epidermal growth factor receptor kinase and the related human epidermal growth factor receptor-2 (HER2, ErbB2) are two growth factor receptors that have implications in cancer. The overexpression or activation of HER2 occurs frequently in breast, ovarian, and lung cancers, making it an important therapeutic target in the treatment of cancer. Blocking HER2-mediated signaling with antibodies or small molecules has been shown to be effective in inhibiting cell growth. After analyzing the crystal structure of the HER2[ndash]herceptin complex, several peptidomimetics (HERP5, 6, and 7) were designed to inhibit HER2-mediated signaling for cell growth. We have used an in silico screening method to investigate the chemical diversity of the designed compounds. autodock software was used to dock the ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708405 Sun, 16 Aug 2009 23:00:00 +0100 2708405 http://www.medworm.com/index.php?rid=2708404&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00851.x This study tests its applicability to several other therapeutic targets: Abl kinase, chitinase, thymidylate synthase, dihydrofolate reductase, and neuraminidase. For the targets where many ([ge]6) mutation data are available to compute the average mutation sensitivity of inhibitors, the total volume of an inhibitor molecule that projects outside the substrate envelope Vout, is found to correlate with average mutation sensitivity. Analysis of a locally computed volume suggests that the same correlation would hold for the other targets, if more extensive mutation data sets were available. It is concluded that the substrate envelope concept offers a promising and easily implemented computational tool for the design of drugs that will tend to resist mutations. Software implementing these calcu... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708404 Sun, 16 Aug 2009 23:00:00 +0100 2708404 http://www.medworm.com/index.php?rid=2708403&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00853.x Deposition of senile plaques composed of fibrillar aggregates of A[beta]-amyloid peptide is a characteristic hallmark of Alzheimer's disease. A widely employed approach in the study of anti-Alzheimer agents involves the identification of substances able to prevent amyloid aggregation, or to disaggregate the amyloid fibrils through a direct structural interaction with the soluble or aggregated forms of the peptide. Here, we report the synthesis of a set of 1,3-dihydro-3,6-disubstituted-imidazo[1,5-c]thiazole-5,7-dione derivatives supporting different alkyl, aryl and alkylamine side chains. The ability of these compounds to interact with the A[beta](25-35) peptide was evaluated using circular dichroism, nuclear magnetic resonance and thioflavin fluorescence spectroscopy. A molecular model fo... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2708403 Sun, 16 Aug 2009 23:00:00 +0100 2708403 http://www.medworm.com/index.php?rid=2648557&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00856.x In this report, we summarize our recent results on the development and biological evaluation of these novel third-generation prodrugs with higher water solubility, higher difference in cytotoxicity between the prodrugs and the corresponding drugs and improved cytotoxicity of the drugs as compared with previous compounds. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2648557 Tue, 28 Jul 2009 23:00:00 +0100 2648557 http://www.medworm.com/index.php?rid=2648556&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00862.x Previous reports describe modulators of X-linked inhibitor of apoptosis (XIAP)[ndash]caspase interaction designed from the AVPI N-terminal peptide sequence of second mitochondria-derived activator of caspase. A fragment-based drug design strategy was initiated to identify therapeutic non-peptidomimetic antagonists of X-linked inhibitor of apoptosis protein[ndash]protein interactions. Fragments that bind to the AVPI binding site of BIR3 (bacculoviral inhibitory repeat) were identified, and to further localize the fragment binding within the AVPI binding site, a point mutation was designed which alters the dynamics of flexible loops and blocks PI region of the binding cleft, thus enabling definition of weakly bound small molecules in the AV portion of the binding cleft. Nuclear magnetic reso... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2648556 Tue, 28 Jul 2009 23:00:00 +0100 2648556 http://www.medworm.com/index.php?rid=2583597&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00846.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2583597 Tue, 07 Jul 2009 23:00:00 +0100 2583597 http://www.medworm.com/index.php?rid=2583596&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00839.x 99mTc-Diethylene triamine pentaacetic acid-bis (amide) conjugates have been synthesized and evaluated as a potential radiopharmaceutical for tumor imaging. The compounds were synthesized by the condensation reaction of DTPA bis(anhydride) with different l-amino acids (methyl tryptophan, and 5-hydroxy tryptophan) and were characterized on the basis of IR, NMR, and Mass spectroscopy. 99mTc-labeled compounds were found stable for about 24 h under physiological conditions with more than 95% radiolabeling yield. Blood kinetic studies of all these complexes showed a bi-exponential pattern as well as quick wash out from the blood circulation. The biological t1/2(F) and t1/2(S) were found to be 20 ± 0.001 min for DTPA-(Me-Trp)2 and 18 ± 0.001 min for DTPA-(5HT)2 and t1/2 (slow) 5 h 45 min ± 0.0... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2583596 Tue, 07 Jul 2009 23:00:00 +0100 2583596 http://www.medworm.com/index.php?rid=2560133&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00845.x Effect of dimethyltin(IV) complexes of different substituted phenyl acrylic acids on the ability of Agrobacterium tumefaciens to cause tumours in plants was studied by using potato discs. The results demonstrated significant inhibition of tumours formation. All the compounds were synthesized and characterized by using analytical techniques, i.e. FTIR, multinuclear NMR (1H, 13C, 19F and 119Sn) and mass spectrometry. These studies explain that dimethyltin(IV) derivatives exist in a deformed octahedral environment known as skew trapezoidal geometry with four strong and two weaker bonds. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2560133 Tue, 30 Jun 2009 23:00:00 +0100 2560133 http://www.medworm.com/index.php?rid=2555499&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00847.x This paper reviews the best known techniques using circular dichroism spectroscopy such as conventional circular dichroism (i.e. electronic circular dichroism), magnetic circular dichroisms (magnetic vibrational circular dichroism, x-ray magnetic circular dichroism), fluorescence detected circular dichroism, near-infrared circular dichroism, vibrational circular dichroism, Fourier transform infrared circular dichroism, high pressure liquid chromatography circular dichroism, stopped-flow circular dichroism, and synchrotron radiation circular dichroism. Also, we have described here the most important applications of circular dichroism spectroscopy in structural biochemistry and nanoscience. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2555499 Mon, 29 Jun 2009 23:00:00 +0100 2555499 http://www.medworm.com/index.php?rid=2516844&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00841.x Protein kinase CK2, also known as casein kinase-2, has been found to be involved in cell growth, proliferation and suppression of apoptosis, which is related to human cancers. The series of compounds were identified as casein kinase-2 inhibitors and their inhibitory activities are a function of a variation of their structures. The current study deals with the pharmacophore identification and, accordingly, the three-dimensional quantitative structure[ndash]activity relationship model development using Pharmacophore Alignment and Scoring Engine. Several hypotheses were developed for the molecular alignments. On the basis of statistical values, the best-fitted model was identified and the same alignment was used for 3D-QSAR using comparative molecular field analysis/comparative molecular simi... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2516844 Thu, 25 Jun 2009 23:00:00 +0100 2516844 http://www.medworm.com/index.php?rid=2503967&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00848.x We report a fragment-based approach to analyze the target selectivity of active compounds. Sets of inhibitors were studied having different activity and selectivity for cathepsins, a family of therapeutically relevant thiol proteases. A systematic analysis was carried out of molecular fragments and atom environment features and their frequency of occurrence for compounds with different selectivity. Fragments extracted from target-selective compounds and independently derived topological features were matched and selectivity markers were identified. Because there is only little overlap between selectivity and other compound set markers, combinations of selectivity set markers could be utilized to predict the selectivity of new cathepsin inhibitors. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2503967 Wed, 24 Jun 2009 23:00:00 +0100 2503967 http://www.medworm.com/index.php?rid=2503972&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00844.x The paper describes a method for the estimation of solubility (log S) of a series of 45 barbiturates employing 26 molecular descriptors. The molecular descriptors used being distance-based topological indices, information indices, valence connectivity index, shape indices, first-order Randic index. In addition, an indicator parameter was also used. The regression analysis has shown that an R2 value of 0.885 was obtained in multi-parametric regression analysis. The results are discussed critically using a variety of statistical parameters. The predictive powers of the models were discussed by using the method of cross-validation. We observed that results obtained using spss and ncss software are identical. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2503972 Sun, 21 Jun 2009 23:00:00 +0100 2503972 http://www.medworm.com/index.php?rid=2503971&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00840.x Oil/water partition coefficient (log P) is one of the key points for lead compound to be drug. In silico log P models based solely on chemical structures have become an important part of modern drug discovery. Here, we report support vector machines, radial basis function neural networks, and multiple linear regression methods to investigate the correlation between partition coefficient and physico-chemical descriptors for a large data set of compounds. The correlation coefficient r 2 between experimental and predicted log P for training and test sets by support vector machines, radial basis function neural networks, and multiple linear regression is 0.92, 0.90, and 0.88, respectively. The results show that non-linear support vector machines derives statistical models that have better pred... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2503971 Sun, 21 Jun 2009 23:00:00 +0100 2503971 http://www.medworm.com/index.php?rid=2503970&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00837.x This paper describes the pharmacological evaluation pertaining to in vivo antiepileptic and locomotor activities, and subsequent QSAR studies on 4,5-diphenyl-1H-imidazole analogues. These two activities on albino mice were determined based on electroshock method and by using actophotometer respectively. Compounds with 4-fluorophenyl, 4-dimethylaminophenyl, 4-hydroxyphenyl and 4-methoxyphenyl substitutions exhibit the highest activity. Compounds with phenyl and 2-nitrophenyl substitutions exhibit the lowest activity in both the cases. Data are divided into training and test/validation sets, the former is used for developing the QSAR and the latter is used for determining the predictive capability of the developed models. The three-parameter model for the antiepileptic activity fits the data... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2503970 Sun, 21 Jun 2009 23:00:00 +0100 2503970 http://www.medworm.com/index.php?rid=2503969&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00843.x The quantitative structure[ndash]activity relationship of the novel 6-naphthylthio 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio) thymine derivatives for prediction of anti-human immunodeficiency virus type 1 activity was studied. The suitable set of the molecular descriptors was calculated and the important descriptors using the variable selections of the stepwise multiple linear regression and the genetic algorithm were selected. A comparison between the attained results indicated the superiority of the genetic algorithm over the stepwise multiple regression method in the feature-selection. The predictive quality of the quantitative structure[ndash]activity relationship models was tested for an external set of eight compounds, randomly chosen out of 39 compounds. The genetic algorithm-multip... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2503969 Sun, 21 Jun 2009 23:00:00 +0100 2503969 http://www.medworm.com/index.php?rid=2503968&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00842.x Several substituted benzenesulfonamides were synthesized by various pathways starting from sulfanilamide. The sulfanilamide diazonium salt was reacted with copper (I) halides, potassium iodide and/or aromatic derivatives, leading to 4-halogeno-, and 4-hydroxy-benzenesulfonamides as well as diazo dyes incorporating sulfamoyl moieties. These sulfonamides were assayed as inhibitors of two physiologically relevant isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), i.e., the cytosolic CA II (ubiquitous), and CA VII (brain-specific enzyme). Good CA inhibitory activity was detected for some of these derivatives, with inhibition constants (Ki) in the range of 17.5[ndash]863 nm against CA II; and 30[ndash]4200 nm against CA VII. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2503968 Sun, 21 Jun 2009 23:00:00 +0100 2503968 http://www.medworm.com/index.php?rid=2503973&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00838.x There is a substantial unmet need for new classes of drugs that block TNF-[alpha]-mediated inflammation, and particularly for small molecule agents that can be taken orally. We have screened a library of natural products against an assay measuring TNF-[alpha] secretion in lipopolysaccharide-stimulated THP-1 cells, seeking compounds capable of interfering with the TNF-[alpha]-inducing transcription factor lipopolysaccharide-induced TNF-[alpha] factor. Among the active compounds were several produced by the kava plant (Piper mysticum), extracts of which have previously been linked to a range of therapeutic effects. When tested in vivo, a representative of these compounds, kavain, was found to render mice immune to lethal doses of lipopolysaccharide. Kavain displays promising pharmaceutical p... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2503973 Mon, 15 Jun 2009 23:00:00 +0100 2503973 http://www.medworm.com/index.php?rid=2413277&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00823.x In this study now, three doubly fluorescent-labeled analogs of neuropeptide Y have been synthesized that still bind to the Y5 receptor with high affinity to investigate the conformation in solution and, for the first time, to probe the conformational changes upon binding of the ligand to its receptor in cell membrane preparations. The results obtained from the fluorescence resonance energy transfer investigations clearly show considerable differences in transfer efficiency that depend both on the solvent as well as on the peptide concentration. However, the studies do not support a pancreatic polypeptide-like folding of neuropeptide Y in the presence of membranes that express the human Y5 receptor subtype. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413277 Sat, 16 May 2009 04:11:26 +0100 2413277 http://www.medworm.com/index.php?rid=2413290&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00824.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413290 Tue, 12 May 2009 04:00:00 +0100 2413290 http://www.medworm.com/index.php?rid=2413289&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00815.x The synthesis of a series of 10-substituted 5,5-dioxo-5,10-dihydro[1,2,4]triazolo[4,3-b][1,2,4]benzothiadiazine coupled with sulfanylacetamido benzothiazole pharmacophores (5a[ndash]g) is described. All the synthesized compounds have been evaluated for their anticancer activity. Most of the compounds showed significant growth inhibitory activity against selected human tumor cell lines. Interestinlgy, one of the synthesized compounds 5d, exhibited GI50 values of 1.4 and 2.1 [mu]m against RPMI-8226 (leukemia) and HOP-62 (lungs) cell lines, respectively. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413289 Tue, 12 May 2009 04:00:00 +0100 2413289 http://www.medworm.com/index.php?rid=2413288&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00822.x In this study, di-n-butyltin(IV) oxide was reacted with the amino glucose analog, cis-4-[N-(1',3',4',6'-tetra-O-benzoyl-2-deoxy-glucopyranosyl)imido]-4-oxo-2-butenoic acid (1a) and o-[N-(1',3',4',6'-tetra-O-benzoyl-2-deoxy-glucopyranosyl) carbamoyl] benzoic acid (2a) to give the complexes bis-{cis-4-[N-(1',3',4',6'-tetra-O-benzoyl-2-deoxy-glucopyranosyl)imido-4-oxo-2-butenoic acid]-di-n-butyltin} carboxylate (1) and bis-{o-[N-(1',3',4',6'-tetra-O-benzoyl-2-deoxy-glucopyranosyl) carbamoyl-benzoic acid]-di-n-butyltin}carboxylate (2). These two compounds were then characterized by IR, NMR and MS. In vitro tests showed that both compounds have high cytotoxicity in four tumor cell lines (P388, HL-60, A549 and BEL-7402). Clonogenic assays demonstrated that both compounds 1 and 2 have hematopoiet... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413288 Tue, 12 May 2009 04:00:00 +0100 2413288 http://www.medworm.com/index.php?rid=2413287&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00819.x A series of novel triazolinones were synthesized and their structures were characterized by 1H NMR, elemental analysis and single-crystal X-ray diffraction analysis. The herbicidal activities were evaluated against Echinochloa crusgalli (L.) Beauv., Digitaria adscendens, Brassica napus and Amaranthus retroflexus. The herbicidal activity data indicated that the title compounds had higher activities with substituted benzyl group moieties than with other groups such as sulfonyl, alkyl, etc. To further investigate the structure[ndash]activity relationship, comparative molecular field analysis was performed on the basis of herbicidal activity data. Both the steric and electronic field distributions of comparative molecular field analysis are in good agreement in this work. The results showed th... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413287 Tue, 12 May 2009 04:00:00 +0100 2413287 http://www.medworm.com/index.php?rid=2413286&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00812.x In this study, four novel analogs (4a[ndash]d) of A771726, the active metabolite of leflunomide were synthesized and examined in vitro for their immunomodulation activity by examining human lymphocyte proliferation and determination of the cytokine interferon-[gamma] concentrations in human lymphocyte cell culture. For this purpose, 5 × 104 human lymphocyte cells were incubated at 37 °C in 5% CO2 with phytohemagglutinin and one of the analogs (concentrations 1[ndash]100 mm), negative controls or cyclosporine (0.1 mm). Effects of the compounds on lymphocyte proliferation and interferon-[gamma] production were determined by MTT assay and enzyme-linked immunosorbent assay, respectively. Our results showed that all four compounds dose-dependently suppressed lymphocyte proliferation. Moreover... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413286 Tue, 12 May 2009 04:00:00 +0100 2413286 http://www.medworm.com/index.php?rid=2413285&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00820.x To find potent fungicides, 35 analogs of diphenyl ketones were synthesized and evaluated for their antifungal activity. These compounds possessed a furyl[ndash]carbonyl[ndash]phenyl skeleton. Bioassay results showed that the synthesized compounds were effective in promoting the antifungal activity of diphenyl ketones. Compound 3 showed the best activity against the four tested fungi (100%, 100%, 100% and 96.4%) and could be used as potent fungicide for further research. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413285 Tue, 12 May 2009 04:00:00 +0100 2413285 http://www.medworm.com/index.php?rid=2413284&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00821.x Ten novel pleuromutilin derivatives with thioether moiety and heterocyclic carboxamide or chloroformate group in the side chain were synthesized and confirmed by 1H NMR, IR and HRMS. The results of the antibacterial activity showed that the title compounds had excellent antibacterial activity against Staphylococcus aureus, among which the MIC of 5f reached 0.03125 [mu]g/mL. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413284 Tue, 12 May 2009 04:00:00 +0100 2413284 http://www.medworm.com/index.php?rid=2413283&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00810.x This study was carried out to elucidate structure of the FRBI-8 and understand its mechanism of inhibiting interaction of FSH to its receptors. Homology modeling predicted that the FRBI-8 adopts a turn and random coil. This is further confirmed by circular dichroism and NMR. Docking studies of the FRBI-8 with reported FSH[ndash]FSHR hormone binding (FSHRHB) domain complex using zdock algorithm revealed that the FRBI-8 binds to FSH[beta]L2[ndash]FSHRHB binding interface which is otherwise known to be crucial for activation of signal transduction cascade. FRBI-8 analogs were designed by replacing the acidic amino acid residues at positions 2, 5 and 6 with Ala, individually. Docking studies revealed that D6A mutant (FRBI-8D6A) had a higher binding affinity than the native FRBI-8. In vitro rad... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413283 Tue, 12 May 2009 04:00:00 +0100 2413283 http://www.medworm.com/index.php?rid=2413282&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00816.x Lung cancer is the second most common cancer in both men (after prostate cancer) and women (after breast cancer). The microtubule-stabilizing taxane such as docetaxel is the only agent currently approved for both first- and second-line treatment of advanced non-small cell lung cancer. Although docetaxel has made significant progress in the treatment of lung cancers either using alone or in combination with various novel targeted agents, its use often results in various undesired side-effects. These limitations have led to the search for new taxane derivatives with fewer side-effects, superior pharmacological properties, and improved anticancer activity to maximize the induced benefits for lung cancer patients. Herein, four series of taxane derivatives were used to correlate their inhibitor... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413282 Tue, 12 May 2009 04:00:00 +0100 2413282 http://www.medworm.com/index.php?rid=2413281&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00811.x dl-Ibuprofen and l-naproxen were coupled with amino acids and other bioactive compounds to provide ibuprofen and naproxen bioconjugates in 61[ndash]95% yield as prodrugs or potential drug candidates. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413281 Tue, 12 May 2009 04:00:00 +0100 2413281 http://www.medworm.com/index.php?rid=2413280&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00813.x N-(4-Arylazobenzoyl)-1H-benzotriazoles 15a, 15b react with dipeptides 12a[ndash]d, (12d+12d') and tripeptides 14a, 14b to give azodye labeled-dipeptides (16a[ndash]e), (16d+16d'), (16e+16e') and -tripeptides 16f, 16g in high yields (73[ndash]93%) with retention of chirality. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413280 Tue, 12 May 2009 04:00:00 +0100 2413280 http://www.medworm.com/index.php?rid=2413279&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00817.x High-content cell-based screens provide a powerful tool to identify new chemicals that interfere with complex biological processes. Here, we describe the identification of a new inhibitor of microtubule dynamics (micropolyin) using a high-content screen. Integrated high-resolution imaging allowed for fast selection of hits and progression to target identification. Treatment of cells with micropolyin efficiently causes a pro-metaphase arrest, with abnormal spindle morphology and with the spindle assembly checkpoint activated. The arrest appears to result from interference of micropolyin with microtubule dynamics. We show in vitro that tubulin is indeed the target of micropolyin and that micropolyin inhibits microtubule polymerization. Our results demonstrate the power of high-content image-... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413279 Tue, 12 May 2009 04:00:00 +0100 2413279 http://www.medworm.com/index.php?rid=2413278&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00818.x In this study, the expressed EC5 has a high thermal stability (Tm = 64.3 °C); it also has two stable conformations at room temperature, which convert to one conformation at approximately 54.5 °C. NMR and FTIR showed that HAV and BLG4 peptides bind to EC5. HSQC-NMR showed that either Asn or Gln of EC5 was involved in the interactions with HAV and BLG4 peptides. EC5 underwent a conformational change upon interaction with the HAV and BLG4 peptides. Finally, the binding properties of both peptides were modeled by docking experiments, and the results suggest that Asn-46 and Asn-75 of EC5 could be involved during the interaction with the peptides and that the Ser and Trp residues of the HAV and BLG4 peptides, respectively, were important for binding to EC5. (Source: Chemical Biology and Drug D... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2413278 Tue, 12 May 2009 04:00:00 +0100 2413278 http://www.medworm.com/index.php?rid=2386531&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00814.x Quantitative structure[ndash]activity relationship analysis has been carried out for 74 diaryl ureas including aminobenzoisoxazole ureas, aminoindazole ureas, aminopyrazolopyridine ureas against vascular endothelial growth factor receptor-2 kinase using both linear and non-linear models. Considering simplicity and predictivity, multivariate linear regression was first employed in combination with various variable selection methods, including forward selection, genetic algorithm and enhanced replacement method based on descriptors generated by e-dragon software. Another model using support vector regression has also been constructed and compared. Performances of these models are rigorously validated by leave-one-out cross-validation, fivefold cross-validation and external validation. The en... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2386531 Mon, 04 May 2009 04:00:00 +0100 2386531 http://www.medworm.com/index.php?rid=2325732&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00805.x Secondary structure motifs and small protein domains can act as building blocks that are isolated and investigated to gain insights into protein global structure but can also modulate interactions with external partners. Most progress has been made in this field using synthetic peptides. Fragmentation of folded proteins by proteolytic enzymes that act preferentially on exposed and less structured sites can help to isolate shorter polypeptides with preserved secondary and tertiary structures that mimic the original protein architecture. Such molecules can be used as probes for structural studies and as tools for in vitro assays to select active fragments useful as agonists or antagonists of the original protein or as scaffolds for the design of more potent and selective ligands. This simple... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2325732 Sat, 11 Apr 2009 22:50:58 +0100 2325732 http://www.medworm.com/index.php?rid=2325747&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00809.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2325747 Mon, 06 Apr 2009 04:00:00 +0100 2325747 http://www.medworm.com/index.php?rid=2325744&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00804.x A fullerene[ndash]isoniazid conjugate has been synthesized by 1, 3 dipolar cycloaddition reaction of fullerene (C60) with isonicotinic acid (4-formyl-benzylidene) hydrazide and N-methylglycine. The identity and purity of the compound was confirmed by elemental analysis, 1H NMR, 13C NMR and MALDI-TOF mass spectral analysis. Stable water suspension, in which the particles of the synthesized conjugate were made to aggregate in nanosize, was successfully tested for antimycobacterial activity against Mycobacterium avium and strains of Mycobacterium tuberculosis[ndash] H37Rv & H6/99 at concentration as low as 0.50 [mu]g/mL. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2325744 Mon, 06 Apr 2009 04:00:00 +0100 2325744 http://www.medworm.com/index.php?rid=2325740&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00806.x There is a need to understand the thermodynamics of interaction of cationic peptides with DNA to design better peptide based non-viral gene delivery vectors. The main aim of this study was to understand the influence of N-terminal hydrophobicity of cationic amphiphilic peptides on thermodynamics of interaction with plasmid DNA. The model peptides used were TATPTD and TATPTDs modified at the N-terminal with hydrophobic amino acids. The thermodynamic binding data from isothermal titration calorimetry were compared with ethidium bromide analysis and ultrafiltration to correlate the binding parameters with the structural features of the various peptides used. It was observed that peptides having a smaller hydrophobic domain at the N-terminal have good DNA condensing ability compared with the o... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2325740 Mon, 06 Apr 2009 04:00:00 +0100 2325740 http://www.medworm.com/index.php?rid=2325736&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00808.x In previous studies we reported on the catalase-like activity and antioxidative properties of a non-heme Fe(III)-tetraaza[14]annulene complex, 5,4-didehydro-5,9,14,18-tetraaza-di(2,2-dimethyl-[5,6]benzo[1,3]dioxolo)[a,h]cyclotetradecene[ndash]Fe(III) chloride (TAA-1/Fe). We proposed that intracellular application of the parent, iron-free tetraaza[14]annulene ligand, TAA-1, as precursor would allow antioxidative defense along two lines, i.e. by chelation of potentially toxic cellular iron ions and, subsequently, by catalase-mimic activity. We here set out to establish whether the active catalase mimic is indeed formed intracellularly when cells are loaded with the ligand. When isolated rat hepatocytes were preloaded with TAA-1, they were protected against iron-induced cell injury and oxidat... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2325736 Mon, 06 Apr 2009 04:00:00 +0100 2325736 http://www.medworm.com/index.php?rid=2248244&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00787.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2248244 Sun, 08 Mar 2009 11:27:46 +0100 2248244 http://www.medworm.com/index.php?rid=2248255&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00798.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2248255 Fri, 06 Mar 2009 05:00:00 +0100 2248255 http://www.medworm.com/index.php?rid=2248254&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00796.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2248254 Fri, 06 Mar 2009 05:00:00 +0100 2248254 http://www.medworm.com/index.php?rid=2248253&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00794.x A new series of 3-(3-ethylphenyl)-2-substituted hydrazino-3H-quinazolin-4-ones were synthesized by reacting the amino group of 2-hydrazino-3-(3-ethylphenyl)-3H-quinazolin-4-one with a variety of aldehydes and ketones. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index behavior. The compound 2-(N'-3-pentylidene-hydrazino)-3-(3-ethylphenyl)-3H-quinazolin-4-one (AS2) emerged as the most active compound in exhibiting analgesic activity and the compound 2-(N'-2-pentylidene-hydrazino)-3-(3-ethylphenyl)-3H-quinazolin-4-one (AS3) emerged as the most active compound in exhibiting anti-inflammatory activity; and these compounds are moderately potent when compared with the reference standard diclofenac sodium. Interestingly, the test compounds showed only mil... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2248253 Fri, 06 Mar 2009 05:00:00 +0100 2248253 http://www.medworm.com/index.php?rid=2248252&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00790.x A nonlinear quantitative structure anti-HIV activity relationship study was presented for modelling and predicting pyrryl aryl sulfones cytotoxicity data. Levenberg-Marquardt artificial neural network was used to link molecular structures and cytotoxicity data. A data set consisting of 27 derivatives of 1-[5-chlorophenyl) sulfonyl]-1H-pyrrole was used in this study. Among a large number of calculated descriptors, only eight significant molecular descriptors were obtained by stepwise regression, as the most feasible descriptors, and then they were used as inputs for neural network. The data set was randomly divided into 20 training and 7 validation sets and the neural network architecture and its parameters were optimized. The prediction ability of the model was evaluated using the validati... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2248252 Fri, 06 Mar 2009 05:00:00 +0100 2248252 http://www.medworm.com/index.php?rid=2248251&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00791.x Thirty six aryloxypropanolamine compounds with cytochrome 2D6 (CYP2D6) inhibitory activity were subjected to molecular shape analysis and molecular field analysis studies to explore the required molecular shape features as well as information on putative interactions with the active site of the enzyme. In addition to the 3D QSAR models, impact of two-dimensional (2D; thermodynamic, structural and topological including E-state parameters) descriptors towards the inhibitory activity was also studied. The whole data set was divided into training (n = 26) and test (n = 10) sets by K-means clustering technique. The chemometric tools used for molecular shape analysis and molecular field analysis were GFA and G/PLS techniques respectively. The G/PLS model derived in molecular field analysis using... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2248251 Fri, 06 Mar 2009 05:00:00 +0100 2248251 http://www.medworm.com/index.php?rid=2248250&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00789.x c-Src kinase play an important role in cell growth and differentiation and its inhibitors can be useful for the treatment of various diseases, including cancer, osteoporosis, and metastatic bone disease. Three dimensional quantitative structure[ndash]activity relationship (3D-QSAR) studies were carried out on quinazolin derivatives inhibiting c-Src kinase. Molecular field analysis (MFA) models with four different alignment techniques, namely, glide, gold, ligandfit and Least squares based methods were developed. glide based MFA model showed better results (Leave one out cross validation correlation coefficient r2cv= 0.923 and non-cross validation correlation coefficient r2 = 0.958) when compared with other models. These results help us to understand the nature of descriptors required for a... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2248250 Fri, 06 Mar 2009 05:00:00 +0100 2248250 http://www.medworm.com/index.php?rid=2248249&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00793.x Forty-eight chalcone analogs were synthesized and their in vitro antibacterial activity against Staphylococcus aureus NCIM 5021, Bacillus subtilis NCIM 2718, Phaseolus vulgaris NCIM 2813, Escherichia coli NCIM 2931, Salmonella typhi 2501 and Enterobacter aerogenes NCIM 5139 were evaluated by microdilution broth assay. Quantitative structure[ndash]activity relationships were developed for all the cases (r 2 = 0.68[ndash]0.79; = 0.58[ndash]0.78; q 2 = 0.51[ndash]0.68; F = 13.02[ndash]61.51). Size, polarizability, electron-donating/withdrawing and hydrophilic nature of the molecule determine the activity against these Gram-positive and Gram-negative bacteria. Staphylococcus aureus was the most and S. typhi was the least hydrophobic of these organisms. These chalcones act better against more h... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2248249 Fri, 06 Mar 2009 05:00:00 +0100 2248249 http://www.medworm.com/index.php?rid=2248248&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00792.x Dye-labelled nucleosides were obtained in 30[ndash]79% (average 45%) yields by treating N-(4-arylazobenzoyl)-1H-benzotriazoles 3a[ndash]b with appropriate nucleosides. Similarly, 3a[ndash]b afforded dye-labelled threoninol conjugates in 55[ndash]89% (average 67%) yields. All novel products were characterized by NMR and elemental analysis. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2248248 Fri, 06 Mar 2009 05:00:00 +0100 2248248 http://www.medworm.com/index.php?rid=2248247&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00797.x An efficient protocol has been developed for the preparation of a series of trans-3-imidazolylflavanones and (Z)-trans-3-imidazolylflavanone oximes, as potential antifungal agents, by the reaction of 2-imidazolyl-2'-hydroxyacetophenone with different benzaldehyde derivatives and subsequence oximation reaction. The stereochemical and conformational aspects of compounds were also assigned by 1H NMR spectroscopy. The aryl group present at C-2 and the imidazole ring present at C-3 were assigned to occupy equatorial position in trans-3-imidazolylflavanones 3 and axial position in (Z)-trans-3-imidazolylflavanone oximes 4. Most of the 3-imidazolylflavanone derivatives containing a substituent on phenyl ring showed significant antifungal activity and modification of the 4-oxo group to oxime or sub... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2248247 Fri, 06 Mar 2009 05:00:00 +0100 2248247 http://www.medworm.com/index.php?rid=2248246&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2009.00786.x The non-receptor Src tyrosine kinase is known to cooperate with the epidermal growth factor receptor in a mechanism leading to invasion and metastasis of solid tumours. With the purpose of developing agents targeted to both epidermal growth factor receptor and Src or related kinases, we embarked on the design of chimeric molecules termed combi-molecules capable of blocking both Src and epidermal growth factor receptor. To this end, we have chosen to design molecules containing a quinazoline moiety (directed at epidermal growth factor receptor) and a 7-phenyl-pyrazolopyrimidine (directed at Src). Molecular modelling showed that the optimal position to attach the linker was the 6-position of the quinazoline and the 9-position of the pyrazolopyrimidine. This has led to the synthesis of SB162,... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=2248246 Fri, 06 Mar 2009 05:00:00 +0100 2248246