Integrating high-content screening and ligand-target prediction to identify mechanism of action
Authors
Young, Daniel W.Bender, Andreas
Hoyt, Jonathan
McWhinnie, Elizabeth
Chirn, Gung-Wei
Tao, Charles Y.
Tallarico, John A.
Labow, Mark A.
Jenkins, Jeremy L.
Mitchison, Timothy J.
Feng, Yan
UMass Chan Affiliations
Department of Cell BiologyDocument Type
Journal ArticlePublication Date
2007-12-11Keywords
*Antineoplastic Agents; Cell Cycle; Cell Nucleus; Cell Proliferation; Cluster Analysis; Computational Biology; DNA Replication; Dose-Response Relationship, Drug; *Drug Design; Hela Cells; Humans; Ligands; Models, Statistical; Molecular Structure; Predictive Value of Tests; Protein Binding; *Small Molecule Libraries; Structure-Activity RelationshipLife Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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.Source
Nat Chem Biol. 2008 Jan;4(1):59-68. Epub 2007 Dec 9. Link to article on publisher's siteDOI
10.1038/nchembio.2007.53Permanent Link to this Item
http://hdl.handle.net/20.500.14038/32865PubMed ID
18066055Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/nchembio.2007.53