N-[2-(1H-benzimidazol-2-yl)ethyl]-2-(2-bromophenoxy)acetamide has been researched along with Chagas-Disease* in 1 studies
1 other study(ies) available for N-[2-(1H-benzimidazol-2-yl)ethyl]-2-(2-bromophenoxy)acetamide and Chagas-Disease
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Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors.
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. Topics: Chagas Disease; Computer Simulation; Cysteine Endopeptidases; Drug Design; Enzyme Inhibitors; High-Throughput Screening Assays; Humans; Protozoan Proteins | 2010 |