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PDBsum entry 3kku
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References listed in PDB file
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Key reference
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Title
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Complementarity between a docking and a high-Throughput screen in discovering new cruzain inhibitors.
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Authors
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R.S.Ferreira,
A.Simeonov,
A.Jadhav,
O.Eidam,
B.T.Mott,
M.J.Keiser,
J.H.Mckerrow,
D.J.Maloney,
J.J.Irwin,
B.K.Shoichet.
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Ref.
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J Med Chem, 2010,
53,
4891-4905.
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PubMed id
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Abstract
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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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