Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors.

Medicinal Chemistry
Informatics

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

Ferreira, Rafaela S; Simeonov, Anton; Jadhav, Ajit; Eidam, Oliv; Mott, Bryan T; Keiser, Michael J; McKerrow, James H; Maloney, David J; Irwin, John J; Shoichet, Brian K;

Keywords

  • Chagas Disease/ drug therapy
  • Computer Simulation
  • Cysteine Endopeptidases/ chemistry
  • Cysteine Endopeptidases/ metabolism
  • Drug Design
  • Enzyme Inhibitors/ chemical synthesis
  • Enzyme Inhibitors/ chemistry
  • Enzyme Inhibitors/ pharmacology
  • High-Throughput Screening Assays
  • Humans
  • Protozoan Proteins/ antagonists & inhibitors
  • Protozoan Proteins/ chemistry
  • Protozoan Proteins/ metabolism

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