Ensemble-based docking: From hit discovery to metabolism and toxicity predictions

Evangelista, Wilfredo; Weir, Rebecca; Ellingson, Sally; Harris, Jason B.; Kapoor, Karan; Smith, Jeremy C.; Baudry, Jerome

doi:10.1016/j.bmc.2016.07.064

Title: Ensemble-based docking: From hit discovery to metabolism and toxicity predictions

Journal Article · Fri Jul 29 00:00:00 EDT 2016 · Bioorganic and Medicinal Chemistry

DOI: https://doi.org/10.1016/j.bmc.2016.07.064 · OSTI ID:1337049

Evangelista, Wilfredo ^[1]; Weir, Rebecca ^[1]; Ellingson, Sally ^[2]; Harris, Jason B. ^[3]; Kapoor, Karan ^[1]; Smith, Jeremy C. ^[3]; Baudry, Jerome ^[1]

Univ. of Tennessee, Knoxville, TN (United States)
Univ. of Kentucky, Lexington, KY (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

The use of ensemble-based docking for the exploration of biochemical pathways and toxicity prediction of drug candidates is described. We describe the computational engineering work necessary to enable large ensemble docking campaigns on supercomputers. We show examples where ensemble-based docking has significantly increased the number and the diversity of validated drug candidates. Finally, we illustrate how ensemble-based docking can be extended beyond hit discovery and toward providing a structural basis for the prediction of metabolism and off-target binding relevant to pre-clinical and clinical trials.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: DOE Office of Science; USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1337049

Journal Information:: Bioorganic and Medicinal Chemistry, Journal Name: Bioorganic and Medicinal Chemistry Journal Issue: 20 Vol. 24; ISSN 0968-0896

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism He, Hui; Weir, Rebecca L.; Toutounchian, Jordan J. PLOS ONE, Vol. 12, Issue 8 https://doi.org/10.1371/journal.pone.0180808	journal	August 2017
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