Abstract
Cell-based screening using phenotypic assays is a useful means of identifying bioactive chemicals for use as tools to elucidate complex cellular processes. However, the chemicals must display sufficient selectivity and their targets have to be identified. We describe how cell-based screening assays can be designed to maximize the likelihood of discovering selective compounds through the choice of positive readouts, low chemical concentrations and long incubation periods. Examining the potency, efficacy and activity range of chemicals can further help set apart those likely to act more specifically. Identifying the cellular targets of active chemicals can be especially demanding. Secondary screens and the cautious use of the candidate approach can help narrow down their mechanisms of action, but biased approaches may lead to the identification of secondary or even irrelevant targets. We discuss strategies for unbiased target identification by sampling potential targets at the genome-wide and proteome-wide levels.
Keywords: Activity-based protein profiling, activity range, Caenorhabditis elegans, candidate approach, chemical biology, chemical-genetic interactions, drug discovery, drug-induced haploinsufficiency, drug targets, proteome profiling
Combinatorial Chemistry & High Throughput Screening
Title: Design of Phenotypic Screens for Bioactive Chemicals and Identification of their Targets by Genetic and Proteomic Approaches
Volume: 11 Issue: 8
Author(s): David C. Schriemer, Danielle Kemmer and Michel Roberge
Affiliation:
Keywords: Activity-based protein profiling, activity range, Caenorhabditis elegans, candidate approach, chemical biology, chemical-genetic interactions, drug discovery, drug-induced haploinsufficiency, drug targets, proteome profiling
Abstract: Cell-based screening using phenotypic assays is a useful means of identifying bioactive chemicals for use as tools to elucidate complex cellular processes. However, the chemicals must display sufficient selectivity and their targets have to be identified. We describe how cell-based screening assays can be designed to maximize the likelihood of discovering selective compounds through the choice of positive readouts, low chemical concentrations and long incubation periods. Examining the potency, efficacy and activity range of chemicals can further help set apart those likely to act more specifically. Identifying the cellular targets of active chemicals can be especially demanding. Secondary screens and the cautious use of the candidate approach can help narrow down their mechanisms of action, but biased approaches may lead to the identification of secondary or even irrelevant targets. We discuss strategies for unbiased target identification by sampling potential targets at the genome-wide and proteome-wide levels.
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Cite this article as:
Schriemer C. David, Kemmer Danielle and Roberge Michel, Design of Phenotypic Screens for Bioactive Chemicals and Identification of their Targets by Genetic and Proteomic Approaches, Combinatorial Chemistry & High Throughput Screening 2008; 11 (8) . https://dx.doi.org/10.2174/138620708785739934
DOI https://dx.doi.org/10.2174/138620708785739934 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
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