title: Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors.
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.
authors.affiliation: Graduate Program in Chemistry and Chemical Biology, University of California San Francisco, California 94158, USA.
authors.forename: Rafaela S
authors.initials: RS
authors.lastname: Ferreira
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: Oliv
authors.initials: O
authors.lastname: Eidam
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Mott
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keiser
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.forename: John J
authors.initials: JJ
authors.lastname: Irwin
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
mesh_terms: D014355:Chagas Disease / Q000188:drug therapy*; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi