Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19Click to copy article linkArticle link copied!
- A. AcharyaA. AcharyaSchool of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, United StatesMore by A. Acharya
- R. AgarwalR. AgarwalUT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United StatesGraduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee 37996, United StatesMore by R. Agarwal
- M. B. BakerM. B. BakerComputer Science and Mathematics Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United StatesMore by M. B. Baker
- J. BaudryJ. BaudryThe University of Alabama in Huntsville, Department of Biological Sciences. 301 Sparkman Drive, Huntsville, Alabama 35899, United StatesMore by J. Baudry
- D. BhowmikD. BhowmikComputational Sciences and Engineering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesMore by D. Bhowmik
- S. BoehmS. BoehmComputer Science and Mathematics Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United StatesMore by S. Boehm
- K. G. BylerK. G. BylerThe University of Alabama in Huntsville, Department of Biological Sciences. 301 Sparkman Drive, Huntsville, Alabama 35899, United StatesMore by K. G. Byler
- S. Y. ChenS. Y. ChenComputational Science Initiative, Brookhaven National Laboratory, Upton, New York 11973, United StatesMore by S. Y. Chen
- L. CoatesL. CoatesNeutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesMore by L. Coates
- C. J. CooperC. J. CooperUT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United StatesGraduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee 37996, United StatesMore by C. J. Cooper
- O. DemerdashO. DemerdashBiosciences Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United StatesMore by O. Demerdash
- I. DaidoneI. DaidoneDepartment of Physical and Chemical Sciences, University of L’Aquila, I-67010 L’Aquila, ItalyMore by I. Daidone
- J. D. EblenJ. D. EblenUT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United StatesThe University of Tennessee, Knoxville. Department of Biochemistry & Cellular and Molecular Biology, 309 Ken and Blaire Mossman Bldg. 1311 Cumberland Avenue, Knoxville, Tennessee 37996, United StatesMore by J. D. Eblen
- S. EllingsonS. EllingsonUniversity of Kentucky, Division of Biomedical Informatics, College of Medicine, UK Medical Center MN 150, Lexington Kentucky 40536, United StatesMore by S. Ellingson
- S. Forli
- J. GlaserJ. GlaserNational Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United StatesMore by J. Glaser
- J. C. GumbartJ. C. GumbartSchool of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, United StatesMore by J. C. Gumbart
- J. GunnelsJ. GunnelsHPC Engineering, Amazon Web Services, Seattle, Washington 98121, United StatesMore by J. Gunnels
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- S. IrleS. IrleComputational Sciences and Engineering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesChemical Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesBredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, Tennessee 37996, United StatesMore by S. Irle
- D. W. KnellerD. W. KnellerNeutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesMore by D. W. Kneller
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- S.-H. LiuS.-H. LiuUT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United StatesThe University of Tennessee, Knoxville. Department of Biochemistry & Cellular and Molecular Biology, 309 Ken and Blaire Mossman Bldg. 1311 Cumberland Avenue, Knoxville, Tennessee 37996, United StatesMore by S.-H. Liu
- J.C. MitchellJ.C. MitchellBiosciences Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United StatesMore by J.C. Mitchell
- G. ParkG. ParkComputational Science Initiative, Brookhaven National Laboratory, Upton, New York 11973, United StatesMore by G. Park
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- A. PavlovaA. PavlovaSchool of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, United StatesMore by A. Pavlova
- L. PetridisL. PetridisUT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United StatesThe University of Tennessee, Knoxville. Department of Biochemistry & Cellular and Molecular Biology, 309 Ken and Blaire Mossman Bldg. 1311 Cumberland Avenue, Knoxville, Tennessee 37996, United StatesMore by L. Petridis
- D. Poole
- L. PouchardL. PouchardComputational Science Initiative, Brookhaven National Laboratory, Upton, New York 11973, United StatesMore by L. Pouchard
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- D. Santos-MartinsD. Santos-MartinsScripps Research, La Jolla, California 92037, United StatesMore by D. Santos-Martins
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- A. SedovaA. SedovaBiosciences Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United StatesMore by A. Sedova
- Y. ShenY. ShenUT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United StatesGraduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee 37996, United StatesMore by Y. Shen
- J. C. Smith*J. C. Smith*Email: [email protected] (J.C.S.)UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United StatesThe University of Tennessee, Knoxville. Department of Biochemistry & Cellular and Molecular Biology, 309 Ken and Blaire Mossman Bldg. 1311 Cumberland Avenue, Knoxville, Tennessee 37996, United StatesMore by J. C. Smith
- M. D. SmithM. D. SmithUT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United StatesThe University of Tennessee, Knoxville. Department of Biochemistry & Cellular and Molecular Biology, 309 Ken and Blaire Mossman Bldg. 1311 Cumberland Avenue, Knoxville, Tennessee 37996, United StatesMore by M. D. Smith
- C. SotoC. SotoComputational Science Initiative, Brookhaven National Laboratory, Upton, New York 11973, United StatesMore by C. Soto
- A. TsarisA. TsarisNational Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United StatesMore by A. Tsaris
- M. ThavappiragasamM. ThavappiragasamBiosciences Division, Oak Ridge National Lab, Oak Ridge, Tennessee 37830, United StatesMore by M. Thavappiragasam
- A. F. Tillack
- J. V. VermaasJ. V. VermaasNational Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United StatesMore by J. V. Vermaas
- V. Q. VuongV. Q. VuongComputational Sciences and Engineering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesChemical Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesBredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, Tennessee 37996, United StatesMore by V. Q. Vuong
- J. YinJ. YinNational Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, United StatesMore by J. Yin
- S. YooS. YooComputational Science Initiative, Brookhaven National Laboratory, Upton, New York 11973, United StatesMore by S. Yoo
- M. ZahranM. ZahranDepartment of Biological Sciences, New York City College of Technology, The City University of New York (CUNY), Brooklyn, New York 11201, United StatesMore by M. Zahran
- L. Zanetti-Polzi
Abstract

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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