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Title: Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19

Abstract

In this work, 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. Additionally, 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)more » methods to cluster MD trajectories and rescore docking poses.« less

Authors:
ORCiD logo [1]; ORCiD logo [2];  [3]; ORCiD logo [4]; ORCiD logo [3]; ORCiD logo [3];  [4];  [5]; ORCiD logo [3]; ORCiD logo [2];  [3]; ORCiD logo [6];  [2];  [7]; ORCiD logo [8]; ORCiD logo [3]; ORCiD logo [1];  [9]; ORCiD logo [3]; ORCiD logo [2] more »; ORCiD logo [3]; ORCiD logo [3];  [10]; ORCiD logo [3];  [10]; ORCiD logo [2];  [3];  [5]; ORCiD logo [2];  [1]; ORCiD logo [2];  [10];  [5]; ORCiD logo [11]; ORCiD logo [3];  [8];  [12]; ORCiD logo [3]; ORCiD logo [2]; ORCiD logo [2]; ORCiD logo [2];  [5];  [13]; ORCiD logo [3];  [8]; ORCiD logo [3];  [2]; ORCiD logo [3];  [5];  [14]; ORCiD logo [15] « less
+ Show Author Affiliations
  1. Georgia Institute of Technology, Atlanta, GA (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
  3. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  4. Univ. of Alabama, Huntsville, AL (United States)
  5. Brookhaven National Lab. (BNL), Upton, NY (United States)
  6. Univ. of L'Aquila (Italy)
  7. Univ. of Kentucky, Lexington, KY (United States)
  8. The Scripps Research Inst., La Jolla, CA (United States)
  9. Amazon Web Services, Seattle, WA (United States)
  10. NVIDIA Corp., Santa Clara, CA (United States)
  11. Argonne National Lab. (ANL), Lemont, IL (United States)
  12. Jubilee Development, Cambridge, MA (United States)
  13. (Aris) [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  14. City Univ. of New York (CUNY), NY (United States)
  15. CNR Inst. of Nanoscience, Modena (Italy)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC); Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH); National Science Foundation (NSF); USDOE Office of Science (SC), Advanced Scientific Computing Research
OSTI Identifier:
1784157
Alternate Identifier(s):
OSTI ID: 1755144; OSTI ID: 1764588
Report Number(s):
BNL-220751-2020-JAAM; BNL-220981-2021-JAAM
Journal ID: ISSN 1549-9596
Grant/Contract Number:  
AC05-00OR22725; AC02-05CH11231; NIH R01-AI148740; 2017219379; SC0012704; R01-AI148740; P30CA177558
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Chemical Information and Modeling
Additional Journal Information:
Journal Volume: 60; Journal Issue: 12; Journal ID: ISSN 1549-9596
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
97 MATHEMATICS AND COMPUTING; reaction mechanisms; ligands; crystal structure; chemical calculations; screening assays

Citation Formats

Acharya, Atanu, Agarwal, Rupesh, Baker, M. B., Baudry, Jerome Y., Bhowmik, Debsindhu, Boehm, Swen, Byler, Kendall G., Chen, S. Y., Coates, Leighton, Cooper, Connor J., Demerdash, Omar N., Daidone, Isabella, Eblen, John D., Ellingson, Sally R., Forli, Stefano, Glaser, Jens, Gumbart, James C., Gunnels, John, Hernandez, Oscar, Irle, Stephan, Kneller, Daniel W., Kovalevsky, Andrii Y., Larkin, Jeffrey, Lawrence, Travis J., LeGrand, Scott, Liu, S.-H. Kevin, Mitchell, Julie C., Park, Gilchan, Parks, Jerry M., Pavlova, Anna, Petridis, Loukas, Poole, Duncan, Pouchard, Line, Ramanathan, Arvind, Rogers, David M., Santos-Martins, Diogo, Scheinberg, Aaron, Sedova, Ada, Shen, Yue, Smith, Jeremy C., Smith, Micholas D., Soto, Carlos, Tsaris, Aristeidis, Thavappiragasam, Mathialakan, Tillack, Andreas F., Vermaas, Josh V., Vuong, Van Quan, Yin, Junqi, Yoo, Shinjae, Zahran, Mai, and Zanetti-Polzi, Laura. Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19. United States: N. p., 2020. Web. doi:10.1021/acs.jcim.0c01010.
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Acharya, Atanu, Agarwal, Rupesh, Baker, M. B., Baudry, Jerome Y., Bhowmik, Debsindhu, Boehm, Swen, Byler, Kendall G., Chen, S. Y., Coates, Leighton, Cooper, Connor J., Demerdash, Omar N., Daidone, Isabella, Eblen, John D., Ellingson, Sally R., Forli, Stefano, Glaser, Jens, Gumbart, James C., Gunnels, John, Hernandez, Oscar, Irle, Stephan, Kneller, Daniel W., Kovalevsky, Andrii Y., Larkin, Jeffrey, Lawrence, Travis J., LeGrand, Scott, Liu, S.-H. Kevin, Mitchell, Julie C., Park, Gilchan, Parks, Jerry M., Pavlova, Anna, Petridis, Loukas, Poole, Duncan, Pouchard, Line, Ramanathan, Arvind, Rogers, David M., Santos-Martins, Diogo, Scheinberg, Aaron, Sedova, Ada, Shen, Yue, Smith, Jeremy C., Smith, Micholas D., Soto, Carlos, Tsaris, Aristeidis, Thavappiragasam, Mathialakan, Tillack, Andreas F., Vermaas, Josh V., Vuong, Van Quan, Yin, Junqi, Yoo, Shinjae, Zahran, Mai, & Zanetti-Polzi, Laura. Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19. United States. https://doi.org/10.1021/acs.jcim.0c01010
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Acharya, Atanu, Agarwal, Rupesh, Baker, M. B., Baudry, Jerome Y., Bhowmik, Debsindhu, Boehm, Swen, Byler, Kendall G., Chen, S. Y., Coates, Leighton, Cooper, Connor J., Demerdash, Omar N., Daidone, Isabella, Eblen, John D., Ellingson, Sally R., Forli, Stefano, Glaser, Jens, Gumbart, James C., Gunnels, John, Hernandez, Oscar, Irle, Stephan, Kneller, Daniel W., Kovalevsky, Andrii Y., Larkin, Jeffrey, Lawrence, Travis J., LeGrand, Scott, Liu, S.-H. Kevin, Mitchell, Julie C., Park, Gilchan, Parks, Jerry M., Pavlova, Anna, Petridis, Loukas, Poole, Duncan, Pouchard, Line, Ramanathan, Arvind, Rogers, David M., Santos-Martins, Diogo, Scheinberg, Aaron, Sedova, Ada, Shen, Yue, Smith, Jeremy C., Smith, Micholas D., Soto, Carlos, Tsaris, Aristeidis, Thavappiragasam, Mathialakan, Tillack, Andreas F., Vermaas, Josh V., Vuong, Van Quan, Yin, Junqi, Yoo, Shinjae, Zahran, Mai, and Zanetti-Polzi, Laura. Wed . "Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19". United States. https://doi.org/10.1021/acs.jcim.0c01010. https://www.osti.gov/servlets/purl/1784157.
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@article{osti_1784157,
title = {Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19},
author = {Acharya, Atanu and Agarwal, Rupesh and Baker, M. B. and Baudry, Jerome Y. and Bhowmik, Debsindhu and Boehm, Swen and Byler, Kendall G. and Chen, S. Y. and Coates, Leighton and Cooper, Connor J. and Demerdash, Omar N. and Daidone, Isabella and Eblen, John D. and Ellingson, Sally R. and Forli, Stefano and Glaser, Jens and Gumbart, James C. and Gunnels, John and Hernandez, Oscar and Irle, Stephan and Kneller, Daniel W. and Kovalevsky, Andrii Y. and Larkin, Jeffrey and Lawrence, Travis J. and LeGrand, Scott and Liu, S.-H. Kevin and Mitchell, Julie C. and Park, Gilchan and Parks, Jerry M. and Pavlova, Anna and Petridis, Loukas and Poole, Duncan and Pouchard, Line and Ramanathan, Arvind and Rogers, David M. and Santos-Martins, Diogo and Scheinberg, Aaron and Sedova, Ada and Shen, Yue and Smith, Jeremy C. and Smith, Micholas D. and Soto, Carlos and Tsaris, Aristeidis and Thavappiragasam, Mathialakan and Tillack, Andreas F. and Vermaas, Josh V. and Vuong, Van Quan and Yin, Junqi and Yoo, Shinjae and Zahran, Mai and Zanetti-Polzi, Laura},
abstractNote = {In this work, 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. Additionally, 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.},
doi = {10.1021/acs.jcim.0c01010},
journal = {Journal of Chemical Information and Modeling},
number = 12,
volume = 60,
place = {United States},
year = {Wed Dec 16 00:00:00 EST 2020},
month = {Wed Dec 16 00:00:00 EST 2020}
}
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  • de Wit, Emmie; Feldmann, Friederike; Cronin, Jacqueline
  • Proceedings of the National Academy of Sciences, Vol. 117, Issue 12
  • DOI: 10.1073/pnas.1922083117

GROMACS: Fast, flexible, and free
journal, January 2005

  • Van Der Spoel, David; Lindahl, Erik; Hess, Berk
  • Journal of Computational Chemistry, Vol. 26, Issue 16
  • DOI: 10.1002/jcc.20291

Molecular dynamics study of human carbonic anhydrase II in complex with Zn2+ and acetazolamide on the basis of all-atom force field simulations
journal, July 2016

Mechanism of glucocerebrosidase activation and dysfunction in Gaucher disease unraveled by molecular dynamics and deep learning
journal, February 2019

  • Romero, Raquel; Ramanathan, Arvind; Yuen, Tony
  • Proceedings of the National Academy of Sciences, Vol. 116, Issue 11
  • DOI: 10.1073/pnas.1818411116

P-LINCS:  A Parallel Linear Constraint Solver for Molecular Simulation
journal, December 2007

  • Hess, Berk
  • Journal of Chemical Theory and Computation, Vol. 4, Issue 1
  • DOI: 10.1021/ct700200b

The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro
journal, May 2020

Cytoplasmic Viral Replication Complexes
journal, July 2010

The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor
journal, October 2003

  • Yang, H.; Yang, M.; Ding, Y.
  • Proceedings of the National Academy of Sciences, Vol. 100, Issue 23
  • DOI: 10.1073/pnas.1835675100

The Probabilistic Relevance Framework: BM25 and Beyond
journal, January 2009

  • Robertson, Stephen; Zaragoza, Hugo
  • Foundations and Trends® in Information Retrieval, Vol. 3, Issue 4
  • DOI: 10.1561/1500000019

Improving AutoDock Vina Using Random Forest: The Growing Accuracy of Binding Affinity Prediction by the Effective Exploitation of Larger Data Sets
journal, February 2015

  • Li, Hongjian; Leung, Kwong-Sak; Wong, Man-Hon
  • Molecular Informatics, Vol. 34, Issue 2-3
  • DOI: 10.1002/minf.201400132

Viracept (Nelfinavir Mesylate, AG1343):  A Potent, Orally Bioavailable Inhibitor of HIV-1 Protease
journal, November 1997

  • Kaldor, Stephen W.; Kalish, Vincent J.; Davies, Jay F.
  • Journal of Medicinal Chemistry, Vol. 40, Issue 24
  • DOI: 10.1021/jm9704098

SWEETLEAD: an In Silico Database of Approved Drugs, Regulated Chemicals, and Herbal Isolates for Computer-Aided Drug Discovery
journal, November 2013

Directory of Useful Decoys, Enhanced (DUD-E): Better Ligands and Decoys for Better Benchmarking
journal, July 2012

  • Mysinger, Michael M.; Carchia, Michael; Irwin, John. J.
  • Journal of Medicinal Chemistry, Vol. 55, Issue 14
  • DOI: 10.1021/jm300687e

Improved Parametrization of Li + , Na + , K + , and Mg 2+ Ions for All-Atom Molecular Dynamics Simulations of Nucleic Acid Systems
journal, December 2011

  • Yoo, Jejoong; Aksimentiev, Aleksei
  • The Journal of Physical Chemistry Letters, Vol. 3, Issue 1
  • DOI: 10.1021/jz201501a

iScreen: world’s first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan
journal, June 2011

  • Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian
  • Journal of Computer-Aided Molecular Design, Vol. 25, Issue 6
  • DOI: 10.1007/s10822-011-9438-9

Parallelization of the MAFFT multiple sequence alignment program
journal, April 2010

CHARMM36m: an improved force field for folded and intrinsically disordered proteins
journal, November 2016

  • Huang, Jing; Rauscher, Sarah; Nawrocki, Grzegorz
  • Nature Methods, Vol. 14, Issue 1
  • DOI: 10.1038/nmeth.4067

Parallel tempering: Theory, applications, and new perspectives
journal, January 2005

  • Earl, David J.; Deem, Michael W.
  • Physical Chemistry Chemical Physics, Vol. 7, Issue 23
  • DOI: 10.1039/b509983h

How Efficient Is Replica Exchange Molecular Dynamics? An Analytic Approach
journal, February 2008

  • Nymeyer, Hugh
  • Journal of Chemical Theory and Computation, Vol. 4, Issue 4
  • DOI: 10.1021/ct7003337

Therapy for Early COVID-19: A Critical Need
journal, December 2020

Comparison of affinity ranking using AutoDock-GPU and MM-GBSA scores for BACE-1 inhibitors in the D3R Grand Challenge 4
journal, November 2019

  • El Khoury, Léa; Santos-Martins, Diogo; Sasmal, Sukanya
  • Journal of Computer-Aided Molecular Design, Vol. 33, Issue 12
  • DOI: 10.1007/s10822-019-00240-w

Remdesivir for the Treatment of Covid-19 — Final Report
journal, November 2020

  • Beigel, John H.; Tomashek, Kay M.; Dodd, Lori E.
  • New England Journal of Medicine, Vol. 383, Issue 19
  • DOI: 10.1056/NEJMoa2007764

Using AutoDock for Ligand‐Receptor Docking
journal, December 2008

Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil
journal, June 2018

Identification of Binding Sites for Efflux Pump Inhibitors of the AcrAB-TolC Component AcrA
journal, February 2019

  • Darzynkiewicz, Zbigniew M.; Green, Adam T.; Abdali, Narges
  • Biophysical Journal, Vol. 116, Issue 4
  • DOI: 10.1016/j.bpj.2019.01.010

An open-source drug discovery platform enables ultra-large virtual screens
journal, March 2020

The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds
journal, March 2015

Evolution of In Silico Strategies for Protein-Protein Interaction Drug Discovery
journal, August 2018

  • Macalino, Stephani Joy Y.; Basith, Shaherin; Clavio, Nina Abigail B.
  • Molecules, Vol. 23, Issue 8
  • DOI: 10.3390/molecules23081963

Multidimensional replica-exchange method for free-energy calculations
journal, October 2000

  • Sugita, Yuji; Kitao, Akio; Okamoto, Yuko
  • The Journal of Chemical Physics, Vol. 113, Issue 15
  • DOI: 10.1063/1.1308516

A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia
journal, November 2016

Best bang for your buck: GPU nodes for GROMACS biomolecular simulations
journal, August 2015

  • Kutzner, Carsten; Páll, Szilárd; Fechner, Martin
  • Journal of Computational Chemistry, Vol. 36, Issue 26
  • DOI: 10.1002/jcc.24030

Neutralizing Antibodies against SARS-CoV-2 and Other Human Coronaviruses
journal, May 2020

Computationally identified novel agonists for GPRC6A
journal, April 2018

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor
journal, March 2020

Crystal structure of Nsp15 endoribonuclease NendoU from SARS‐CoV ‐2
journal, May 2020

  • Kim, Youngchang; Jedrzejczak, Robert; Maltseva, Natalia I.
  • Protein Science, Vol. 29, Issue 7
  • DOI: 10.1002/pro.3873

Structural and Functional Evidence for Testosterone Activation of GPRC6A in Peripheral Tissues
journal, December 2015

  • Pi, Min; Kapoor, Karan; Wu, Yunpeng
  • Molecular Endocrinology, Vol. 29, Issue 12
  • DOI: 10.1210/me.2015-1161

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV
journal, January 2020

Ensemble-based docking: From hit discovery to metabolism and toxicity predictions
journal, October 2016

  • Evangelista, Wilfredo; Weir, Rebecca L.; Ellingson, Sally R.
  • Bioorganic & Medicinal Chemistry, Vol. 24, Issue 20
  • DOI: 10.1016/j.bmc.2016.07.064

Rapid calculation of RMSDs using a quaternion-based characteristic polynomial
journal, June 2005

  • Theobald, Douglas L.
  • Acta Crystallographica Section A Foundations of Crystallography, Vol. 61, Issue 4
  • DOI: 10.1107/S0108767305015266

Structure-based design of broadly protective group a streptococcal M protein-based vaccines
journal, January 2017

PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations
journal, May 2007

  • Dolinsky, T. J.; Czodrowski, P.; Li, H.
  • Nucleic Acids Research, Vol. 35, Issue Web Server
  • DOI: 10.1093/nar/gkm276

Prediction of peptide binding to MHC using machine learning with sequence and structure-based feature sets
journal, April 2020

  • Aranha, Michelle P.; Spooner, Catherine; Demerdash, Omar
  • Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1864, Issue 4
  • DOI: 10.1016/j.bbagen.2020.129535

Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China
journal, March 2020

FAST: FAST Analysis of Sequences Toolbox
journal, May 2015

  • Lawrence, Travis J.; Kauffman, Kyle T.; Amrine, Katherine C. H.
  • Frontiers in Genetics, Vol. 6
  • DOI: 10.3389/fgene.2015.00172

Density-Functional Tight-Binding Combined with the Fragment Molecular Orbital Method
journal, October 2014

  • Nishimoto, Yoshio; Fedorov, Dmitri G.; Irle, Stephan
  • Journal of Chemical Theory and Computation, Vol. 10, Issue 11
  • DOI: 10.1021/ct500489d

The PDBbind Database:  Methodologies and Updates
journal, June 2005

  • Wang, Renxiao; Fang, Xueliang; Lu, Yipin
  • Journal of Medicinal Chemistry, Vol. 48, Issue 12
  • DOI: 10.1021/jm048957q

SuperDRUG2: a one stop resource for approved/marketed drugs
journal, November 2017

  • Siramshetty, Vishal B.; Eckert, Oliver Andreas; Gohlke, Björn-Oliver
  • Nucleic Acids Research, Vol. 46, Issue D1
  • DOI: 10.1093/nar/gkx1088

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
journal, April 2020

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