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Evidence-Based and Quantitative Prioritization of Tool Compounds in Phenotypic Drug Discovery

Wang, Yuan and Cornett, Allen and King, Frederick and Mao, Yi and Nigsch, Florian and Paris, Greg and Mcallister, Gregory and Jenkins, Jeremy (2016) Evidence-Based and Quantitative Prioritization of Tool Compounds in Phenotypic Drug Discovery. Cell Chemical Biology, 23 (7). pp. 862-874. ISSN 24519456

Abstract

The use of potent and selective chemical tools with well-defined targets can help elucidate biological processes driving phenotypes in phenotypic screens. However, identification of selective compounds en masse to create targeted screening sets is non-trivial. A systematic approach is needed to prioritize probes, which prevents the repeated use of published but unselective compounds. Here we performed a meta-analysis of integrated large-scale, heterogeneous bioactivity data to create an evidence-based, quantitative metric to systematically rank tool compounds for targets. Our tool score (TS) was then tested on hundreds of compounds by assessing their activity profiles in a panel of 41 cell-based pathway assays. We demonstrate that high-TS tools show more reliably selective phenotypic profiles than lower-TS compounds. Additionally we highlight frequently tested compounds that are non-selective tools and distinguish target family polypharmacology from cross-family promiscuity. TS can therefore be used to prioritize compounds from heterogeneous databases for phenotypic screening.

Item Type: Article
Date Deposited: 24 Jul 2016 00:45
Last Modified: 24 Jul 2016 00:45
URI: https://oak.novartis.com/id/eprint/28985

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