Evaluation of virtual screening as a tool for chemical genetic applications.
A collection of over 50,000 functionally annotated drugs, clinical candidates, and endogenous ligands was docked in silico against nine binding sites from seven protein targets, representing diverse function and structure, namely the sulfotransferases SULT1E1 and SULT1A3, the histone methyltransferase EHMT1, the histone acetyltransferase MYST3, and the nuclear hormone receptors ERalpha, PPARgamma, and TRbeta. For 5 of the 9 virtual screens, compounds that docked best to the receptors clearly recapitulated known biological functions of the genes or identified novel biology subsequently validated in a separate experimental study. In two cases, the hit list indicated some relevant but isolated biological functions which would probably have been ignored a priori, and selected compounds were completely unrelated to gene function for the last two virtual screens. This study demonstrates that virtual screening of pharmacologically annotated compound libraries can be used to derive target biology.
Campagna-Slater
Valérie
V
Structural Genomics Consortium, University of Toronto, MaRS Centre, South Tower, seventh floor, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
Schapira
Matthieu
M
D019295:Computational Biology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005823:Genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014584:User-Computer Interface
D004791:Enzyme Inhibitors; D006657:Histones; D018160:Receptors, Cytoplasmic and Nuclear; D015238:Sulfotransferases