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Integrating high-content screening and ligand-target prediction to identify mechanism of action.

Young, Daniel and Bender, Andreas and Hoyt, Jonathan and McWhinnie, Elizabeth and Chirn, Gung-Wei and Tao, Charles and Tallarico, John and Labow, Mark and Jenkins, Jeremy and Mitchison, Timothy and Feng, Yan (2008) Integrating high-content screening and ligand-target prediction to identify mechanism of action. Nature Chemical Biology, 4 (1). pp. 59-68. ISSN 1552-4469

Abstract

High-content screening is transforming drug discovery by enabling simultaneous measurement of multiple features of cellular phenotype that are relevant to therapeutic and toxic activities of compounds. High-content screening studies typically generate immense datasets of image-based phenotypic information, and how best to mine relevant phenotypic data is an unsolved challenge. Here, we introduce factor analysis as a data-driven tool for defining cell phenotypes and profiling compound activities. This method allows a large data reduction while retaining relevant information, and the data-derived factors used to quantify phenotype have discernable biological meaning. We used factor analysis of cells stained with fluorescent markers of cell cycle state to profile a compound library and cluster the hits into seven phenotypic categories. We then compared phenotypic profiles, chemical similarity and predicted protein binding activities of active compounds. By integrating these different descriptors of measured and potential biological activity, we can effectively draw mechanism-of-action inferences.

Item Type: Article
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Date Deposited: 14 Dec 2009 14:01
Last Modified: 31 Jan 2013 01:19
URI: https://oak.novartis.com/id/eprint/340

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