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Complementarity Between a Docking and a High-Throughput Screen in Discovering New Cruzain Inhibitors

R. S. Ferreira,A. Simeonov,A. Jadhav,O. Eidam,B. Mott,Michael J. Keiser,J. McKerrow,D. Maloney,J. Irwin,B. Shoichet

Published 2010 in Journal of Medicinal Chemistry

ABSTRACT

Virtual and high-throughput screens (HTS) should have complementary strengths and weaknesses, but studies that prospectively and comprehensively compare them are rare. We undertook a parallel docking and HTS screen of 197861 compounds against cruzain, a thiol protease target for Chagas disease, looking for reversible, competitive inhibitors. On workup, 99% of the hits were eliminated as false positives, yielding 146 well-behaved, competitive ligands. These fell into five chemotypes: two were prioritized by scoring among the top 0.1% of the docking-ranked library, two were prioritized by behavior in the HTS and by clustering, and one chemotype was prioritized by both approaches. Determination of an inhibitor/cruzain crystal structure and comparison of the high-scoring docking hits to experiment illuminated the origins of docking false-negatives and false-positives. Prioritizing molecules that are both predicted by docking and are HTS-active yields well-behaved molecules, relatively unobscured by the false-positives to which both techniques are individually prone.

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