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Automated Planar Electrode Electrophysiology in Drug Discovery: Examples of the Use of QPatch in Basic Characterization and High Content Screening on Na(v), K(Ca)2.3, and K(v)11.1 Channels.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Planar chip technology has strongly facilitated the progress towards fully automated electrophysiological systems that, in contrast to the traditional patch clamp technology, have the capability of parallel compound testing. The throughput has been increased from testing below 10 compounds per day to a realized capacity approaching high throughput levels. Many pharmaceutical companies have implemented automated planar chip electrophysiology in their drug discovery process, particularly at the levels of lead optimization, secondary screening and safety testing, whereas primary screening is generally not performed. In th...
Source: Combinatorial Chemistry and High Throughput Screening - January 22, 2009 Category: Chemistry Authors: Korsgaard MP, Strøbæk D, Christophersen P Tags: Comb Chem High Throughput Screen Source Type: journals

Ion channels: applications in ion channel drug discovery.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19149487 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening)
Source: Combinatorial Chemistry and High Throughput Screening - January 1, 2009 Category: Chemistry Authors: Krafte DS Tags: Comb Chem High Throughput Screen Source Type: journals

Evolution of the human ion channel set.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Ion channels are intimately involved in virtually every physiological process of consequence in humans. Their importance is underscored by the identification of numerous "channelopathies", human diseases caused by ion channel mutations. Ion Channels have consequently been viewed as fertile ground for drug discovery and, indeed, they represent one of the largest target classes for current medicines. The future prospects of ion channels as a target class are tied to the functional characterization of the human ion channel set on a genomic scale. The focus of this review is to describe the molecular diversity and conserva...
Source: Combinatorial Chemistry and High Throughput Screening - January 1, 2009 Category: Chemistry Authors: Jegla TJ, Zmasek CM, Batalov S, Nayak SK Tags: Comb Chem High Throughput Screen Source Type: journals

Port-a-Patch and Patchliner: High Fidelity Electrophysiology for Secondary Screening and Safety Pharmacology.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Ion channel dysfunction is known to underlie several acute and chronic disorders and, therefore, ion channels have gained increased interest as drug targets. During the past decade, ion channel screening platforms have surfaced that enable high throughput drug screening from a more functional perspective. These two factors taken together have further inspired the development of more refined screening platforms, such as the automated patch clamp platforms described in this article. Approximately six years ago, Nanion introduced its entry level device for automated patch clamping - the Port-a-Patch. With this device, Nan...
Source: Combinatorial Chemistry and High Throughput Screening - January 1, 2009 Category: Chemistry Authors: Farre C, Haythornthwaite A, Haarmann C, Stoelzle S, Kreir M, George M, Brüggemann A, Fertig N Tags: Comb Chem High Throughput Screen Source Type: journals

High throughput electrophysiology with Xenopus oocytes.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe here the main features and potential applications of OpusXpress, an efficient commercially available system for automated recording from Xenopus oocytes. We show some types of data that have been gathered by this system and review realized and potential applications. PMID: 19149490 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening)
Source: Combinatorial Chemistry and High Throughput Screening - January 1, 2009 Category: Chemistry Authors: Papke RL, Smith-Maxwell C Tags: Comb Chem High Throughput Screen Source Type: journals

HCN Channels as Targets for Drug Discovery.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hyperpolarization- and Cyclic Nucleotide-gated (HCN) channels are a family of six transmembrane domain, single pore-loop, hyperpolarization activated, non-selective cation channels. The HCN family consists of four members (HCN1-4). HCN channels represent the molecular correlates of I(h) (also known as 'funny' I(f) and 'queer' I(q)), a hyperpolarization-activated current best known for its role in controlling heart rate and in the regulation of neuronal resting membrane potential and excitability. A significant body of molecular and pharmacological evidence is now emerging to support a role for these channels in the fun...
Source: Combinatorial Chemistry and High Throughput Screening - January 1, 2009 Category: Chemistry Authors: Maher MP, Wu NT, Guo HQ, Dubin AE, Chaplan SR, Wickenden AD Tags: Comb Chem High Throughput Screen Source Type: journals

The chiptip: a novel tool for automated patch clamp.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
To facilitate automated patch clamp measurements of ion channels in cells, the development of an all-glass Chiptip pipette is reported that may be combined with the previously described Flip-the-Tip technology. A single measurement requires less than 50 cells, and the addition of drugs for screening can be limited to very low volumes down to 1 microL. This apparatus is suitable for the study small cells, subcellular organelles and bacteria. PMID: 19149493 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening)
Source: Combinatorial Chemistry and High Throughput Screening - January 1, 2009 Category: Chemistry Authors: Lepple-Wienhues A, Lassen D, Hümmer A, Czubayko U, Knirsch M, Golubovic A Tags: Comb Chem High Throughput Screen Source Type: journals

QPatch: The Missing Link Between HTS and Ion Channel Drug Discovery.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We present detailed analyses of the QPatch features and results in case studies in which secondary screening assays were successfully developed for a voltage-gated calcium channel and a ligand-gated TRP channel. The increase in throughput compared to conventional patch clamp with the same cells was approximately 10-fold. We conclude that the QPatch, combining high data quality and speed with user friendliness and suitability for a wide array of ion channels, resides on the cutting edge of automated patch clamp technology and plays a pivotal role in expediting ion channel drug discovery. PMID: 19149494 [PubMed - in proc...
Source: Combinatorial Chemistry and High Throughput Screening - January 1, 2009 Category: Chemistry Authors: Mathes C, Friis S, Finley M, Liu Y Tags: Comb Chem High Throughput Screen Source Type: journals

Use of planar array electrophysiology for the development of robust ion channel cell lines.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This article focuses on several complex and difficult to express ion channels and illustrates how improved stable cell lines can be obtained by integration of planar array electrophysiology systems into the cell line generation process per se. By embedding this approach at multiple stages (e.g., during development of the expression strategy, during screening and validation of clonal lines, and during characterisation of the final cell line), the cycle time and success rate in obtaining robust expression of complex multi-subunit channels can be significantly improved. We also review how recent advances in this technology (e...
Source: Combinatorial Chemistry and High Throughput Screening - January 1, 2009 Category: Chemistry Authors: Clare JJ, Chen MX, Downie DL, Trezise DJ, Powell AJ Tags: Comb Chem High Throughput Screen Source Type: journals

Sodium channel inhibitor drug discovery using automated high throughput electrophysiology platforms.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Voltage dependent sodium channels are widely recognized as valuable targets for the development of therapeutic interventions for neuroexcitatory disorders such as epilepsy and pain as well as cardiac arrhythmias. An ongoing challenge for sodium channel drug discovery is the ability to readily evaluate state dependent interactions, which are known to underlie inhibition by many clinically used local anesthetic, antiepileptic and antiarrhythmic sodium channel blockers. While patch-clamp electrophysiology is still considered the most effective way of measuring ion channel function and pharmacology, it does not have the th...
Source: Combinatorial Chemistry and High Throughput Screening - January 1, 2009 Category: Chemistry Authors: Castle N, Printzenhoff D, Zellmer S, Antonio B, Wickenden A, Silvia C Tags: Comb Chem High Throughput Screen Source Type: journals

Ranking of pharmaceuticals detected in the environment: aggregation and weighting procedures.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Pharmaceuticals are omnipresent in waste-water world-wide. Research has shown that many pharmaceuticals are not completely removed during wastewater treatment, and as a result, this has led to their occurrence being reported in waste water treatment plant effluents, rivers and lakes, and more rarely in groundwater and in drinking water. Hence, it is only logical that pharmaceutical residues in the environment and their potential toxic effects have been recognized as one of the emerging research areas in environmental chemistry. A lack of data, especially ecotoxicological and fate data on pharmaceuticals, is evident. Th...
Source: Combinatorial Chemistry and High Throughput Screening - December 1, 2008 Category: Chemistry Authors: Voigt K, Brüggemann R Tags: Comb Chem High Throughput Screen Source Type: journals

Partial Order Theory Applied to QSPR-QSAR Studies.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
There exists a great amount of information on ranking methods provided in the literature, a new appealing methodology that is generally dealt in a so mathematical fashion. Ranking strategies are applied in a wide range of scientific fields, such as Decision Support, Toxicology, Environmental Research, Analytical Chemistry, Food Chemistry, QSPR-QSAR, etc. When contrasted to other multi-criteria data analyzes, Partial Order Ranking results in a very transparent and suitable way to perform comparisons among a set of objects (such as molecules) according to their attributes (molecular descriptors) values. The scope of this...
Source: Combinatorial Chemistry and High Throughput Screening - December 1, 2008 Category: Chemistry Authors: Duchowicz PR, Castr EA Tags: Comb Chem High Throughput Screen Source Type: journals

Assessment of chemicals applying partial order ranking techniques.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This review summarizes the use of partial order ranking (POR) techniques for the assessment of chemicals. Simple partial order ranking may advantageously be applied to give the single chemicals investigated an identity in relation to other substances. Thus, it constitutes an effective tool for the prioritization of chemicals, e.g., based on their PBT (Persistence, Bioaccumulating, Toxicity) characteristics. In more elaborate cases where a larger number of descriptors are taken into account, e.g., comprising physico-chemical characteristics, atmospheric parameters, geospecific factors, and possibly socio-economic factor...
Source: Combinatorial Chemistry and High Throughput Screening - December 1, 2008 Category: Chemistry Authors: Carlsen L Tags: Comb Chem High Throughput Screen Source Type: journals

Combinatorial Saturation Mutagenesis of the Myceliophthora thermophila Laccase T2 Mutant: the Connection between the C-Terminal Plug and the Conserved (509)VSG(511) Tripeptide.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A mutant laccase from the Ascomycete Myceliophthora thermophila has been submitted to iterative cycles of combinatorial saturation mutagenesis through in vivo overlap extension in Saccharomyces cerevisiae. Over 180,000 clones were explored, among which the S510G mutant revealed a direct interaction between the conserved (509)VSG(511) tripeptide, located in the neighborhood of the T1 site, and the C-terminal plug. The K(m)(O)(2) value of the mutant increased 1.5-fold, and the electron transfer pathway between the reducing substrate and the T1 copper ion was altered, improving the catalytic efficiency towards non-phenoli...
Source: Combinatorial Chemistry and High Throughput Screening - December 1, 2008 Category: Chemistry Authors: Zumárraga M, Vaz Domínguez C, Camarero S, Shleev S, Polaina J, Martínez-Arias A, Ferrer M, De Lacey AL, Fernández VM, Ballesteros A, Plou FJ, Alcalde M Tags: Comb Chem High Throughput Screen Source Type: journals

Optimization and validation of two miniaturized glucocerebrosidase enzyme assays for high throughput screening.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Glucocerebrosidase (GC) catalyzes the hydrolysis of beta-glucocerebroside to glucose and ceramide in lysosomes. Mutations in the glucocerebrosidase gene (GBA) result in Gaucher disease, an autosomal recessive lysosomal storage disorder. Many of the mutations encountered in patients with Gaucher disease are missense alterations that may cause misfolding, decreased stability and/or mistrafficking of this lysosomal protein. Some inhibitors of GC have been shown to act as chemical chaperones, stabilizing the conformation of mutant proteins and thus restoring their function. High throughput screening (HTS) of small molecule...
Source: Combinatorial Chemistry and High Throughput Screening - December 1, 2008 Category: Chemistry Authors: Urban DJ, Zheng W, Goker-Alpan O, Jadhav A, Lamarca ME, Inglese J, Sidransky E, Austin CP Tags: Comb Chem High Throughput Screen Source Type: journals

Closing the Gap between Centralized and Decentralized Compound Management Approaches.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The demand for organized storage concepts to maintain, collect and distribute compounds has grown not only at pharmaceutical companies, but also at smaller research organizations and academic laboratories where there is the demand to store and retrieve substances systematically. However, budget limitations have prevented these smaller groups from buying costly storage systems offered by specialized commercial vendors. On the other hand, within pharmaceutical companies a need for inexpensive and flexible storage concepts has developed and complements the existing automated archives. For reasons of efficiency, most compa...
Source: Combinatorial Chemistry and High Throughput Screening - December 1, 2008 Category: Chemistry Authors: Andreae MR, Steiner T, Hueber M, Schopfer U, Smith R, Igo D, Cantrell D, Hohos A, Kiwanuka A Tags: Comb Chem High Throughput Screen Source Type: journals

Cytomic Screening of Immuno-Modulating Activity Compounds from Calocedrus formosana.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Procedures for cytomic screening were developed for identifying compounds with immuno-modulating properties from the crude extracts of natural products. Human peripheral blood mononuclear cells (hPB-MNCs) were first cultured with different natural crude extracts for 12 hours in culture media. By analyzing the expression of early activation CD69 marker, the potential immuno-activating properties of ethanol extracts of Calocedrus formosana were observed. By the double staining of antibodies recognizing CD69 and specific cell type markers, the increase of CD69 expressions was observed in CD3 and CD14 cell populations. To ...
Source: Combinatorial Chemistry and High Throughput Screening - December 1, 2008 Category: Chemistry Authors: Tsai CC, Chen CJ, Tseng HW, Hua KF, Tsai RY, Lai MH, Chao LK, Chen ST Tags: Comb Chem High Throughput Screen Source Type: journals

Synthetic applications of polystyrene-supported 1,1,3,3-tetramethylguanidine.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study evidenced the effectiveness and versatility of this new member of the supported guanidine superbases as an attractive candidate to replace the bases usually employed in organic synthesis during the implementation of environmentally friendly preparative processes. PMID: 19075606 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening)
Source: Combinatorial Chemistry and High Throughput Screening - December 1, 2008 Category: Chemistry Authors: Coelho A, Crespo A, Fernández F, Biagini P, Stefanachi A, Sotelo E Tags: Comb Chem High Throughput Screen Source Type: journals

Partial order in chemistry.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 18991572 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening)
Source: Combinatorial Chemistry and High Throughput Screening - November 1, 2008 Category: Chemistry Authors: Brüggemann R Tags: Comb Chem High Throughput Screen Source Type: journals

Kronecker-product periodic systems of small gas-phase molecules and the search for order in atomic ensembles of any phase.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The periodic law, manifested in the chart of the elements, is so fundamental in chemistry and related areas of physics that the question arises "Might periodicity among molecules also be embodied in a periodic system?" This review paper details how a particular periodic system of gas-phase diatomic molecules, allowing for the forecasting of thousands of new data, was developed. It can include ionized and even quarked-nuclei molecules and it coincides with locality (averaging) and the additivity found in some data; it has interesting vector properties, and it may be related in challenging ways to partial order. The revi...
Source: Combinatorial Chemistry and High Throughput Screening - November 1, 2008 Category: Chemistry Authors: Hefferlin R Tags: Comb Chem High Throughput Screen Source Type: journals

Combinatorial properties of graphs and groups of physico-chemical interest.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Combinatorial properties of graphs and groups of physico-chemical interest are described. A type of mathematical modeling is applied which involves "translating" algebraic expressions into graphs. The idea is applied to both graph theory and group theory. The former topic includes objects of importance in physics and chemistry such as trees, polyomino graphs, king boards, etc. Our study along these lines emphasizes nonadjacency relations, graph-generation, quasicrystals, continued fractions, fractals, and general ordering schemes of graphs. The second part of the paper considers certain colored graphs as models of seve...
Source: Combinatorial Chemistry and High Throughput Screening - November 1, 2008 Category: Chemistry Authors: El-Basil S Tags: Comb Chem High Throughput Screen Source Type: journals

Combinatorics of reaction-network posets.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Reaction networks are viewed as derived from ordinary molecular structures related in reactant-product pairs so as to manifest a chemical super-structure. Such super-structures then are candidates for applications in a general combinatoric chemistry. Notable additional characterization of a reaction super-structure occurs when such reaction graphs are directed, as for example when there is progressive substitution (or addition) on a fixed molecular skeleton. Such a set of partially ordered entities is in mathematics termed a poset, which further manifests a number of special properties, as then might be utilized in dif...
Source: Combinatorial Chemistry and High Throughput Screening - November 1, 2008 Category: Chemistry Authors: Klein DJ, Ivanciuc T, Ryzhov A, Ivanciuc O Tags: Comb Chem High Throughput Screen Source Type: journals

A Hitchhiker's Guide to Poset Ranking.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
When ranking objects (like chemicals, geographical sites, river sections, etc.) by multicriteria analysis, it is in most cases controversial and difficult to find a common scale among the criteria of concern. Therefore, ideally, one should not resort to such artificial additional constraints. The theory of partially ordered sets (or posets for short) provides a solid formal framework for the ranking of objects without assigning a common scale and/or weights to the criteria, and therefore constitutes a valuable alternative to traditional approaches. In this paper, we aim to give a comprehensive literature review on the ...
Source: Combinatorial Chemistry and High Throughput Screening - November 1, 2008 Category: Chemistry Authors: De Loof K, De Baets B, De Meyer H, Brüggemann R Tags: Comb Chem High Throughput Screen Source Type: journals

New operations for informative combination of two partial order relations with illustrations on pollution data.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We discuss various ways in which to construct and process partial order relations or partially ordered sets (posets) in the context of ranking objects on the basis of multiple criteria. Oftentimes, it is undesirable or even impossible to devise a weighting scheme to compute a final score on the basis of the criteria. An alternative is then to restrict oneself to the information contained in the partial ordering of all objects implied by the criteria. We will consider some ways in which one can exploit partial order relations to determine a ranking of a collection of objects. More exactly, we will examine how to combine...
Source: Combinatorial Chemistry and High Throughput Screening - November 1, 2008 Category: Chemistry Authors: Rademaker M, De Baets B, De Meyer H Tags: Comb Chem High Throughput Screen Source Type: journals

Basic principles of hasse diagram technique in chemistry.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Principles of partial order applied to ranking are explained. The Hasse diagram technique (HDT) is the application of partial order theory based on a data matrix. In this paper, HDT is introduced in a stepwise procedure, and some elementary theorems are exemplified. The focus is to show how the multivariate character of a data matrix is realized by HDT and in which cases one should apply other mathematical or statistical methods. Many simple examples illustrate the basic theoretical ideas. Finally, it is shown that HDT is a useful alternative for the evaluation of antifouling agents, which was originally performed by a...
Source: Combinatorial Chemistry and High Throughput Screening - November 1, 2008 Category: Chemistry Authors: Brüggemann R, Voigt K Tags: Comb Chem High Throughput Screen Source Type: journals

Chemogenomics: a discipline at the crossroad of high throughput technologies, biomarker research, combinatorial chemistry, genomics, cheminformatics, bioinformatics and artificial intelligence.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Chemogenomics is the study of the interaction of functional biological systems with exogenous small molecules, or in broader sense the study of the intersection of biological and chemical spaces. Chemogenomics requires expertises in biology, chemistry and computational sciences (bioinformatics, cheminformatics, large scale statistics and machine learning methods) but it is more than the simple apposition of each of these disciplines. Biological entities interacting with small molecules can be isolated proteins or more elaborate systems, from single cells to complete organisms. The biological space is therefore analyzed...
Source: Combinatorial Chemistry and High Throughput Screening - September 1, 2008 Category: Chemistry Authors: Maréchal E Tags: Comb Chem High Throughput Screen Source Type: journals

Expanding the chemical space in practice: diversity-oriented synthesis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Diversity-Oriented Synthesis (DOS) aims to broaden the frontier of accessible collections of complex and diverse small molecules. This review endeavours to dissect the DOS concept through three elements of diversity: building block, stereochemistry, and skeleton. Recent examples in the literature that emphasize the efficient combinations of these elements to generate diversity are reported. PMID: 18795878 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening)
Source: Combinatorial Chemistry and High Throughput Screening - September 1, 2008 Category: Chemistry Authors: Peuchmaur M, Wong YS Tags: Comb Chem High Throughput Screen Source Type: journals

Cell-Based Assays in Practice: Cell Markers from Autofluorescent Proteins of the GFP-Family.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The more recently discovered anthozoan fluorescent proteins (FPs) and the classic Aequorea victoria Green Fluorescent Protein (avGFP) as well as their derivatives have become versatile tools as live cell markers in fluorescence microscopy. In this review, we show the use of these FPs in drug discovery assays. Assay examples are given for the application of FPs in multiplexed imaging, as photosensitizers, as fluorescent timers, as pulse-chase labels and for robotically integrated compound testing. The development of fast microscopic imaging devices has enabled the application of automated fluorescence microscopy combine...
Source: Combinatorial Chemistry and High Throughput Screening - September 1, 2008 Category: Chemistry Authors: Wolff M, Kredel S, Wiedenmann J, Nienhaus GU, Heilker R Tags: Comb Chem High Throughput Screen Source Type: journals

Design of Phenotypic Screens for Bioactive Chemicals and Identification of their Targets by Genetic and Proteomic Approaches.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe how cell-based screening assays can be designed to maximize the likelihood of discovering selective compounds through the choice of positive readouts, low chemical concentrations and long incubation periods. Examining the potency, efficacy and activity range of chemicals can further help set apart those likely to act more specifically. Identifying the cellular targets of active chemicals can be especially demanding. Secondary screens and the cautious use of the candidate approach can help narrow down their mechanisms of action, but biased approaches may lead to the identification of secondary or even irrelevant...
Source: Combinatorial Chemistry and High Throughput Screening - September 1, 2008 Category: Chemistry Authors: Schriemer DC, Kemmer D, Roberge M Tags: Comb Chem High Throughput Screen Source Type: journals

Chemogenomics and Cancer Chemotherapy: Cell-Based Assays to Screen for Small Molecules that Impair Microtubule Dynamics.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Microtubules are still a promising target for new therapeutic agents. Thus, there is a continuous interest for compounds able to modify microtubule assembly, either by interacting directly with tubulin, or by interacting with microtubules regulators. Because of its dynamic characteristics, the microtubule cytoskeleton is a suitable target for small molecules that rapidly diffuse in the cell cytoplasm. Moreover, compounds targeting the microtubule cytoskeleton have proved to be valuable tools for basic research in cell biology. In this paper, after a short presentation of the apparent molecular pathways involved in the ...
Source: Combinatorial Chemistry and High Throughput Screening - September 1, 2008 Category: Chemistry Authors: Lafanechère L Tags: Comb Chem High Throughput Screen Source Type: journals

Chemogenomics and parasitology: small molecules and cell-based assays to study infectious processes.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Infectious diseases caused by protozoan parasites - malaria, sleeping sickness, leishmaniasis, Chagas' disease, toxoplasmosis - remain chronic problems for humanity. We lack vaccines and have limited drug options effective against protozoa. Research into anti-protozoan drugs has accelerated with improved in vitro cultivation methods, enhanced genetic accessibility, completed genome sequences for key protozoa, and increased prominence of protozoan diseases on the agendas of well-resourced public figures and foundations. Concurrent advances in high-throughput screening (HTS) technologies and availability of diverse small...
Source: Combinatorial Chemistry and High Throughput Screening - September 1, 2008 Category: Chemistry Authors: Muskavitch MA, Barteneva N, Gubbels MJ Tags: Comb Chem High Throughput Screen Source Type: journals

Plant pathogen recognition as a natural, original and simple model for chemogenomics: a brief overview of cell-based assays to screen for peptides acting as plant defense activators.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
As plants lack a circulatory system and adaptive immune system, they have evolved their own defense systems distinct from animals, in which each plant cell is capable of defending itself from pathogens. Plants induce a number of defense responses, which are triggered by a variety of molecules derived from pathogenic microorganisms, referred to as microbe-associated molecular patterns (MAMPs), including peptides, proteins, lipopolysaccharide, beta-glucan, chitin, and ergosterol. The interaction between plants and chemicals in the context of plant defense represents a "natural" and simple model for chemogenomics, at the ...
Source: Combinatorial Chemistry and High Throughput Screening - September 1, 2008 Category: Chemistry Authors: Miyashita M, Miyagawa H Tags: Comb Chem High Throughput Screen Source Type: journals

Building a biological space based on protein sequence similarities and biological ontologies.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Assignment of function to protein sequence is a task of growing importance in the life sciences, as new high-throughput sequencing DNA technologies generate ever increasing quantities of genomic and meta-genomic data. Patterns within the sequence space, caused by the evolutionary conservation and assembly of protein domains, make possible the inference of function from sequence similarity. Clustering similar sequences is a useful technique for finding conserved sequences; the CluSTr database is a publicly-available database arranging proteins in a hierarchy structured by similarity. The protein classification tool Inte...
Source: Combinatorial Chemistry and High Throughput Screening - September 1, 2008 Category: Chemistry Authors: Kersey P, Lonsdale D, Mulder NJ, Petryszak R, Apweiler R Tags: Comb Chem High Throughput Screen Source Type: journals

Building a chemical space based on fragment descriptors.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This article reviews the application of fragment descriptors at different stages of virtual screening: filtering, similarity search, and direct activity assessment using QSAR/QSPR models. Several case studies are considered. It is demonstrated that the power of fragment descriptors stems from their universality, very high computational efficiency, simplicity of interpretation and versatility. PMID: 18795885 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening)
Source: Combinatorial Chemistry and High Throughput Screening - September 1, 2008 Category: Chemistry Authors: Baskin I, Varnek A Tags: Comb Chem High Throughput Screen Source Type: journals

A Ligand-Based Approach to Mining the Chemogenomic Space of Drugs.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The practical implementation and validation of a ligand-based approach to mining the chemogenomic space of drugs is presented and applied to the in silico target profiling of 767 drugs against 684 targets of therapeutic relevance. The results reveal that drugs targeting aminergic G protein-coupled receptors (GPCRs) show the most promiscuous pharmacological profiles. The detection of cross-pharmacologies between aminergic GPCRs and the opioid, sigma, NMDA, and 5-HT3 receptors aggravate the potential promiscuity of those drugs, predominantly including analgesics, antidepressants, and antipsychotics. PMID: 18795886 [P...
Source: Combinatorial Chemistry and High Throughput Screening - September 1, 2008 Category: Chemistry Authors: Gregori-Puigjané E, Mestres J Tags: Comb Chem High Throughput Screen Source Type: journals

Machine learning for in silico virtual screening and chemical genomics: new strategies.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Support vector machines and kernel methods belong to the same class of machine learning algorithms that has recently become prominent in both computational biology and chemistry, although both elds have largely ignored each other. These methods are based on a sound mathematical and computationally efficient framework that implicitly embeds the data of interest, respectively proteins and small molecules, in high-dimensional feature spaces where various classification or regression tasks can be performed with linear algorithms. In this review, we present the main ideas underlying these approaches, survey how both the "bi...
Source: Combinatorial Chemistry and High Throughput Screening - September 1, 2008 Category: Chemistry Authors: Vert JP, Jacob L Tags: Comb Chem High Throughput Screen Source Type: journals

Cell-based screening.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 18694385 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening)
Source: Combinatorial Chemistry and High Throughput Screening - August 1, 2008 Category: Chemistry Authors: Zaman GJ Tags: Comb Chem High Throughput Screen Source Type: journals

Functional cell-based assays in microliter volumes for ultra-high throughput screening.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Functional cell-based assays have gained increasing importance for microplate-based high throughput screening (HTS). The use of high-density microplates, most prominently 1536-well plates, and miniaturized assay formats allow screening of comprehensive compound collections with more than 1 million compounds at ultra-high throughput, i.e. in excess of 100,000 samples per day. uHTS operations with numerous campaigns per year should generally support this throughput at all different steps of the process, including the underlying compound logistics, the (automated) testing of the corporate compound collection in the bioass...
Source: Combinatorial Chemistry and High Throughput Screening - August 1, 2008 Category: Chemistry Authors: Wunder F, Kalthof B, Müller T, Hüser J Tags: Comb Chem High Throughput Screen Source Type: journals

Fluorescent probes for cellular assays.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A fluorescent probe is a fluorophore designed to localize within a specific region of a biological specimen or to respond to a specific stimulus. Fluorescent probes have been used for nearly a century to study cellular processes due to their exquisite sensitivity and selectivity. Fluorescent probes have also gained in popularity as safety and environmental concerns over the use of radioactive probes have grown. At the same time, cellular assays are being more widely used now than ever before. This review will give a broad overview of types of fluorescent probes, types of fluorescent assays, and their application in cel...
Source: Combinatorial Chemistry and High Throughput Screening - August 1, 2008 Category: Chemistry Authors: Hanson GT, Hanson BJ Tags: Comb Chem High Throughput Screen Source Type: journals

Ion channel screening.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Ion channels are attractive targets for drug discovery with recent estimates indicating that voltage and ligand-gated channels account for the third and fourth largest gene families represented in company portfolios after the G protein coupled and nuclear hormone receptor families. A historical limitation on ion channel targeted drug discovery in the form of the extremely low throughput nature of the gold standard assay for assessing functional activity, patch clamp electrophysiology in mammalian cells, has been overcome by the implementation of multi-well plate format cell-based screening strategies for ion channels. ...
Source: Combinatorial Chemistry and High Throughput Screening - August 1, 2008 Category: Chemistry Authors: Dunlop J, Bowlby M, Peri R, Tawa G, Larocque J, Soloveva V, Morin J Tags: Comb Chem High Throughput Screen Source Type: journals

High-content analysis of kinase activity in cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
High-content analysis (HCA) is a term used to describe techniques involving multiplexed analysis of fluorescent markers to measure multiple cellular responses to biological stimuli or drug treatment. HCA is usually based on automated microscopy or related technologies, and its value lies in providing multiparametric information on single cells within a population. During the last decade, several HCA approaches have been developed and applied to assess cellular mechanism of action of pharmacologically relevant compounds identified through biochemical screening or similar in vitro methods. With automation and instrument ...
Source: Combinatorial Chemistry and High Throughput Screening - August 1, 2008 Category: Chemistry Authors: Gasparri F, Sola F, Bandiera T, Moll J, Galvani A Tags: Comb Chem High Throughput Screen Source Type: journals

Profiling of Multiple Signal Pathway Activities by Multiplexing Antibody and GFP-Based Translocation Assays.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Multiplexing of GFP based and immunofluorescence translocation assays enables easy acquisition of multiple readouts from the same cell in a single assay run. Immunofluorescence assays monitor translocation, phosphorylation, and up/down regulation of endogenous proteins. GFP-based assays monitor translocation of stably expressed GFP-fusion proteins. Such assays may be multiplexed along (vertical), across (horizontal), and between (branch) signal pathways. Examples of these strategies are presented: 1) The MK2-GFP assay monitors translocation of MK2-GFP from the nucleus to the cytoplasm in response to stimulation of the ...
Source: Combinatorial Chemistry and High Throughput Screening - August 1, 2008 Category: Chemistry Authors: Henriksen U, Fog J, Loechel F, Præstegaard M Tags: Comb Chem High Throughput Screen Source Type: journals

A Miniaturized Glucocorticoid Receptor Translocation Assay Using Enzymatic Fragment Complementation Evaluated with qHTS.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Nuclear translocation is an important step in glucocorticoid receptor (GR) signaling and assays that measure this process allow the identification of nuclear receptor ligands independent of subsequent functional effects. To facilitate the identification of GR-translocation agonists, an enzyme fragment complementation (EFC) cell-based assay was scaled to a 1536-well plate format to evaluate 9,920 compounds using a quantitative high throughput screening (qHTS) strategy where compounds are assayed at multiple concentrations. In contrast to conventional assays of nuclear translocation the qHTS assay described here was enab...
Source: Combinatorial Chemistry and High Throughput Screening - August 1, 2008 Category: Chemistry Authors: Zhu PJ, Zheng W, Auld DS, Jadhav A, Macarthur R, Olson KR, Peng K, Dotimas H, Austin CP, Inglese J Tags: Comb Chem High Throughput Screen Source Type: journals

The Use of Immortalized Cell Lines in GPCR Screening: The Good, Bad and Ugly.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
For most membrane-bound molecular targets, including G protein linked receptors (GPCRs), the optimal approach in drug discovery involves the use of cell based high throughput screening (HTS) technologies to identify compounds that modulate target activity. Most GPCRs have been cloned and can therefore be routinely expressed in immortalized cell lines. These cells can be easily and rapidly grown in unlimited quantities making them ideal for use in current HTS technologies. A significant advantage of this approach is that immortalized recombinant cells provide a homogenous background for expression of the target which gr...
Source: Combinatorial Chemistry and High Throughput Screening - August 1, 2008 Category: Chemistry Authors: Eglen RM, Gilchrist A, Reisine T Tags: Comb Chem High Throughput Screen Source Type: journals

An overview of drug screening using primary and embryonic stem cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cellular technologies are widely used in drug discovery to treat human diseases. Most studies involve the expression of recombinant targets in immortalized cells and measure drug interactions using simple, quantifiable responses. Such cells are also amenable to high throughput screening (HTS) methods. However, the cell phenotype employed in HTS is often determined by the assay technology available, rather than the physiological relevance of the cell background. They are, therefore, suboptimal surrogates for cells that accurately reflect human diseases. Consequently, there is growing interest in adopting primary and emb...
Source: Combinatorial Chemistry and High Throughput Screening - August 1, 2008 Category: Chemistry Authors: Eglen RM, Gilchrist A, Reisine T Tags: Comb Chem High Throughput Screen Source Type: journals

Label-free cell-based functional assays.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This article will describe these technologies and their applications in measuring cell proliferation, cell attachment and spreading, cell apoptosis and their application for several receptor target classes, including receptor tyrosine kinases and G protein-coupled receptors. The potential utility and drawbacks of these tools for high throughput screening, directed screening and compound profiling will also be discussed. PMID: 18694394 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening)
Source: Combinatorial Chemistry and High Throughput Screening - August 1, 2008 Category: Chemistry Authors: Minor LK Tags: Comb Chem High Throughput Screen Source Type: journals

Development of selective high affinity antagonists, agonists, and radioligands for the P2Y1 receptor.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The P2Y(1) receptor is a member of the P2Y family of nucleotide-activated G protein-coupled receptors, and it is an important therapeutic target based on its broad tissue distribution and essential role in platelet aggregation. We have designed a set of highly selective and diverse pharmacological tools for studying the P2Y(1) receptor using a rational approach to ligand design. Based on the discovery that bisphosphate analogues of the P2Y(1) receptor agonist, ADP, are partial agonists/competitive antagonists of this receptor, an iterative approach was used to develop competitive antagonists with enhanced affinity and ...
Source: Combinatorial Chemistry and High Throughput Screening - July 1, 2008 Category: Chemistry Authors: Houston D, Costanzi S, Jacobson KA, Harden TK Tags: Comb Chem High Throughput Screen Source Type: journals

GPCR High Throughput Screening (Part 1).Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 18673268 [PubMed - in process] (Source: Combinatorial Chemistry and High Throughput Screening)
Source: Combinatorial Chemistry and High Throughput Screening - July 1, 2008 Category: Chemistry Authors: Willard FS, Siderovski DP Tags: Comb Chem High Throughput Screen Source Type: journals

Development of Selective High Affinity Antagonists, Agonists, and Radioligands for the P2Y(1) Receptor.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The P2Y(1) receptor is a member of the P2Y family of nucleotide-activated G protein-coupled receptors, and it is an important therapeutic target based on its broad tissue distribution and essential role in platelet aggregation. We have designed a set of highly selective and diverse pharmacological tools for studying the P2Y(1) receptor using a rational approach to ligand design. Based on the discovery that bisphosphate analogues of the P2Y(1) receptor agonist, ADP, are partial agonists/competitive antagonists of this receptor, an iterative approach was used to develop competitive antagonists with enhanced affinity and ...
Source: Combinatorial Chemistry and High Throughput Screening - July 1, 2008 Category: Chemistry Authors: Houston D, Costanzi S, Jacobson KA, Harden TK Tags: Comb Chem High Throughput Screen Source Type: journals