Article abstract
Nature Chemical Biology 4, 59 - 68 (2008)
Published online: 9 December 2007 | doi:10.1038/nchembio.2007.53
Integrating high-content screening and ligand-target prediction to identify mechanism of action
Daniel W Young1,2,5, Andreas Bender3, Jonathan Hoyt1, Elizabeth McWhinnie1, Gung-Wei Chirn1, Charles Y Tao1, John A Tallarico4, Mark Labow1, Jeremy L Jenkins3, Timothy J Mitchison2 & Yan Feng1
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.
- Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
- Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
- Lead Discovery Informatics, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
- Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
- Present address: Wolf, Greenfield & Sacks, P.C., 600 Atlantic Avenue, Boston, Massachusetts 02210, USA.
Correspondence to: Yan Feng1 e-mail: yan.feng@novartis.com
Correspondence to: Jeremy L Jenkins3 e-mail: jeremy.jenkins@novartis.com
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