1222659-69-9Relevant academic research and scientific papers
Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors
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.
supporting information; experimental part, p. 4891 - 4905 (2010/10/19)
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.
