title: Ensemble-based docking: From hit discovery to metabolism and toxicity predictions.
abstract: This paper describes and illustrates the use of ensemble-based docking, i.e., using a collection of protein structures in docking calculations for hit discovery, the exploration of biochemical pathways and toxicity prediction of drug candidates. 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.
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, The University of Tennessee, Knoxville, TN, United States; UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN, United States.
authors.forename: Wilfredo
authors.initials: W
authors.lastname: Evangelista
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, The University of Tennessee, Knoxville, TN, United States; UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN, United States.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Weir
authors.affiliation: UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN, United States; Genome Science and Technology, University of Tennessee, Knoxville, TN, United States; Division of Biomedical Informatics, College of Medicine, University of Kentucky and Cancer Research Informatics, Markey Cancer Center, Lexington, KY, United States.
authors.forename: Sally R
authors.initials: SR
authors.lastname: Ellingson
authors.affiliation: UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN, United States; Genome Science and Technology, University of Tennessee, Knoxville, TN, United States.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Harris
authors.affiliation: UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN, United States; Genome Science and Technology, University of Tennessee, Knoxville, TN, United States.
authors.forename: Karan
authors.initials: K
authors.lastname: Kapoor
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, The University of Tennessee, Knoxville, TN, United States; UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN, United States; Genome Science and Technology, University of Tennessee, Knoxville, TN, United States. Electronic address: smithjc@ornl.gov.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Smith
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, The University of Tennessee, Knoxville, TN, United States; UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN, United States; Genome Science and Technology, University of Tennessee, Knoxville, TN, United States. Electronic address: jbaudry@utk.edu.
authors.forename: Jerome
authors.initials: J
authors.lastname: Baudry
mesh_terms: D055808:Drug Discovery; D062105:Molecular Docking Simulation; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations
keywords: Computational drug discovery; Docking; Drug discovery; Hit discovery; Lead discovery; Toxicity