title: Using high-throughput screening data to discriminate compounds with single-target effects from those with side effects.
abstract: The most desirable compound leads from high-throughput assays are those with novel biological activities resulting from their action on a single biological target. Valuable resources can be wasted on compound leads with significant 'side effects' on additional biological targets; therefore, technical refinements to identify compounds that primarily have effects resulting from a single target are needed. This study explores the use of multiple assays of a chemical library and a statistic based on entropy to identify lead compound classes that have patterns of assay activity resulting primarily from small molecule action on a single target. This statistic, called the coincidence score, discriminates with 88% accuracy compound classes known to act primarily on a single target from compound classes with significant side effects on nonhomologous targets. Furthermore, a significant number of the compound classes predicted to have primarily single-target effects contain known bioactive compounds. We also show that a compound's known biological target or mechanism of action can often be suggested by its pattern of activities in multiple assays.
authors.affiliation: Howard Hughes Medical Institute, 12 Oxford Street, Cambridge, Massachusetts 02138, Harvard Institute of Chemistry and Cell Biology, 250 Longwood Avenue, SGMB-604, Boston, Massachusetts 02115, USA. Klekota@gmail.com
authors.forename: Justin
authors.initials: J
authors.lastname: Klekota
authors.forename: Erik
authors.initials: E
authors.lastname: Brauner
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Roth
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D064420:Drug-Related Side Effects and Adverse Reactions; D004364:Pharmaceutical Preparations / Q000737:chemistry; D010600:Pharmacology; D013816:Thermodynamics
chemical_list: D004364:Pharmaceutical Preparations