Successful virtual screening of a chemical database for farnesyltransferase inhibitor leads

Virtual screening of chemical databases is an emerging approach in drug dis covery that uses computers to dock chemicals into the active site of a drug target to identify leads through evaluation of binding affinities of the c hemicals. However, there are concerns about the validity and scope of the r eported virtual screens due to lack of studies to show that randomly select ed chemicals are not equally active and due to the fact that metalloprotein s were rarely used as drug targets. We have performed a virtual screening o f a chemical database to identify prototypic inhibitors of farnesyltransfer ase (FT) with zinc present in the active site. Among the 21 compounds ident ified by computers, four inhibited FT in vitro with IC50 values in the rang e from 25 to 100 mu M. The most potent inhibitor also inhibited FT in human lung cancer cells. In contrast, none of 21 randomly selected compounds hav e an IC50 lower than 100 mu M. The results demonstrate the validity of virt ual screening and the feasibility of applications of this approach to metal loprotein drug targets, such as matrix metalloproteinases, farnesyltransfer ase, and HIV-1 integrase, for the treatments of cardiovascular diseases, ca ncers, and AIDS.