PMID: 11931626Apr 5, 2002Paper

A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening

Journal of Medicinal Chemistry
Susan L McGovernBrian K Shoichet

Abstract

High-throughput and virtual screening are widely used to discover novel leads for drug design. On examination, many screening hits appear non-drug-like: they act noncompetitively, show little relationship between structure and activity, and have poor selectivity. Attempts to develop these peculiar molecules into viable leads are often futile, and much time can be wasted on the characterization of these "phony" hits. Despite their common occurrence, the mechanism of action of these promiscuous molecules remains unknown. To investigate this problem, 45 diverse screening hits were studied. Fifteen of these were previously reported as inhibitors of various receptors, including beta-lactamase, malarial protease, dihydrofolate reductase, HIV Tar RNA, thymidylate synthase, kinesin, insulin receptor, tyrosine kinases, farnesyltransferase, gyrase, prions, triosephosphate isomerase, nitric oxide synthase, phosphoinositide 3-kinase, and integrase; 30 were from an in-house screening library of a major pharmaceutical company. In addition to their original targets, 35 of these 45 compounds were shown to inhibit several unrelated model enzymes. These 35 screening hits included compounds, such as fullerenes, dyes, and quercetin, that have repe...Continue Reading

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