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Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19
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    Computational Biochemistry

    Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19
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    • A. Acharya
      A. Acharya
      School of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
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    • R. Agarwal
      R. Agarwal
      UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
      Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee 37996, United States
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    • M. B. Baker
      M. B. Baker
      Computer Science and Mathematics Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United States
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    • J. Baudry
      J. Baudry
      The University of Alabama in Huntsville, Department of Biological Sciences. 301 Sparkman Drive, Huntsville, Alabama 35899, United States
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    • D. Bhowmik
      D. Bhowmik
      Computational Sciences and Engineering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
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    • S. Boehm
      S. Boehm
      Computer Science and Mathematics Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United States
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    • K. G. Byler
      K. G. Byler
      The University of Alabama in Huntsville, Department of Biological Sciences. 301 Sparkman Drive, Huntsville, Alabama 35899, United States
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    • S. Y. Chen
      S. Y. Chen
      Computational Science Initiative, Brookhaven National Laboratory, Upton, New York 11973, United States
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    • L. Coates
      L. Coates
      Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
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    • C. J. Cooper
      C. J. Cooper
      UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
      Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee 37996, United States
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    • O. Demerdash
      O. Demerdash
      Biosciences Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United States
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    • I. Daidone
      I. Daidone
      Department of Physical and Chemical Sciences, University of L’Aquila, I-67010 L’Aquila, Italy
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    • J. D. Eblen
      J. D. Eblen
      UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
      The University of Tennessee, Knoxville. Department of Biochemistry & Cellular and Molecular Biology, 309 Ken and Blaire Mossman Bldg. 1311 Cumberland Avenue, Knoxville, Tennessee 37996, United States
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    • S. Ellingson
      S. Ellingson
      University of Kentucky, Division of Biomedical Informatics, College of Medicine, UK Medical Center MN 150, Lexington Kentucky 40536, United States
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    • S. Forli
      S. Forli
      Scripps Research, La Jolla, California 92037, United States
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    • J. Glaser
      J. Glaser
      National Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
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    • J. C. Gumbart
      J. C. Gumbart
      School of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
    • J. Gunnels
      J. Gunnels
      HPC Engineering, Amazon Web Services, Seattle, Washington 98121, United States
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    • O. Hernandez
      O. Hernandez
      Computer Science and Mathematics Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United States
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    • S. Irle
      S. Irle
      Computational Sciences and Engineering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      Chemical Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, Tennessee 37996, United States
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    • D. W. Kneller
      D. W. Kneller
      Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
    • A. Kovalevsky
      A. Kovalevsky
      Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
    • J. Larkin
      J. Larkin
      NVIDIA Corporation, Santa Clara, California 95051, United States
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    • T. J. Lawrence
      T. J. Lawrence
      Biosciences Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United States
    • S. LeGrand
      S. LeGrand
      NVIDIA Corporation, Santa Clara, California 95051, United States
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    • S.-H. Liu
      S.-H. Liu
      UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
      The University of Tennessee, Knoxville. Department of Biochemistry & Cellular and Molecular Biology, 309 Ken and Blaire Mossman Bldg. 1311 Cumberland Avenue, Knoxville, Tennessee 37996, United States
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    • J.C. Mitchell
      J.C. Mitchell
      Biosciences Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United States
    • G. Park
      G. Park
      Computational Science Initiative, Brookhaven National Laboratory, Upton, New York 11973, United States
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    • J.M. Parks
      J.M. Parks
      UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
      Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee 37996, United States
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    • A. Pavlova
      A. Pavlova
      School of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
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    • L. Petridis
      L. Petridis
      UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
      The University of Tennessee, Knoxville. Department of Biochemistry & Cellular and Molecular Biology, 309 Ken and Blaire Mossman Bldg. 1311 Cumberland Avenue, Knoxville, Tennessee 37996, United States
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    • D. Poole
      D. Poole
      NVIDIA Corporation, Santa Clara, California 95051, United States
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    • L. Pouchard
      L. Pouchard
      Computational Science Initiative, Brookhaven National Laboratory, Upton, New York 11973, United States
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    • A. Ramanathan
      A. Ramanathan
      Data Science and Learning Division, Argonne National Lab, Lemont, Illinois 60439, United States
    • D. M. Rogers
      D. M. Rogers
      National Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
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      D. Santos-Martins
      Scripps Research, La Jolla, California 92037, United States
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      A. Scheinberg
      Jubilee Development, Cambridge Massachusetts 02139, United States
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      A. Sedova
      Biosciences Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United States
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      Y. Shen
      UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
      Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee 37996, United States
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    • J. C. Smith*
      J. C. Smith
      UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
      The University of Tennessee, Knoxville. Department of Biochemistry & Cellular and Molecular Biology, 309 Ken and Blaire Mossman Bldg. 1311 Cumberland Avenue, Knoxville, Tennessee 37996, United States
      *Email: [email protected] (J.C.S.)
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    • M. D. Smith
      M. D. Smith
      UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
      The University of Tennessee, Knoxville. Department of Biochemistry & Cellular and Molecular Biology, 309 Ken and Blaire Mossman Bldg. 1311 Cumberland Avenue, Knoxville, Tennessee 37996, United States
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      C. Soto
      Computational Science Initiative, Brookhaven National Laboratory, Upton, New York 11973, United States
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      A. Tsaris
      National Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
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      M. Thavappiragasam
      Biosciences Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United States
    • A. F. Tillack
      A. F. Tillack
      Scripps Research, La Jolla, California 92037, United States
    • J. V. Vermaas
      J. V. Vermaas
      National Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
    • V. Q. Vuong
      V. Q. Vuong
      Computational Sciences and Engineering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      Chemical Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, Tennessee 37996, United States
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      J. Yin
      National Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United States
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      S. Yoo
      Computational Science Initiative, Brookhaven National Laboratory, Upton, New York 11973, United States
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      M. Zahran
      Department of Biological Sciences, New York City College of Technology, The City University of New York (CUNY), Brooklyn, New York 11201, United States
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    • L. Zanetti-Polzi
      L. Zanetti-Polzi
      CNR Institute of Nanoscience, I-41125 Modena, Italy
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    Journal of Chemical Information and Modeling

    Cite this: J. Chem. Inf. Model. 2020, 60, 12, 5832–5852
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    https://doi.org/10.1021/acs.jcim.0c01010
    Published December 16, 2020
    Copyright © 2020 American Chemical Society

    Abstract

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    We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

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