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High Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Non-Covalent Inhibitor

View ORCID ProfileAustin Clyde, Stephanie Galanie, Daniel W. Kneller, Heng Ma, Yadu Babuji, Ben Blaiszik, Alexander Brace, Thomas Brettin, Kyle Chard, Ryan Chard, Leighton Coates, Ian Foster, Darin Hauner, Vilmos Kertesz, Neeraj Kumar, Hyungro Lee, Zhuozhao Li, Andre Merzky, Jurgen G. Schmidt, Li Tan, Mikhail Titov, Anda Trifan, Matteo Turilli, Hubertus Van Dam, Srinivas C. Chennubhotla, Shantenu Jha, Andrey Kovalevsky, View ORCID ProfileArvind Ramanathan, Marti Head, Rick Stevens
doi: https://doi.org/10.1101/2021.03.27.437323
Austin Clyde
aData Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA
bDepartment of Computer Science, University of Chicago, Chicago, IL 60615, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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  • ORCID record for Austin Clyde
Stephanie Galanie
dBiosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, 37831 USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Daniel W. Kneller
cNeutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, TN, 37831, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Heng Ma
aData Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Yadu Babuji
aData Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA
lGlobus, University of Chicago, Chicago, IL 60615, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Ben Blaiszik
aData Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA
lGlobus, University of Chicago, Chicago, IL 60615, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Alexander Brace
aData Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Thomas Brettin
iComputing Environment and Life Sciences Directorate, Argonne National Laboratory, Lemont, IL 60439, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Kyle Chard
aData Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA
bDepartment of Computer Science, University of Chicago, Chicago, IL 60615, USA
lGlobus, University of Chicago, Chicago, IL 60615, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Ryan Chard
aData Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA
lGlobus, University of Chicago, Chicago, IL 60615, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Leighton Coates
kSecond Target Station, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Ian Foster
aData Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA
bDepartment of Computer Science, University of Chicago, Chicago, IL 60615, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Darin Hauner
qComputational Biology Group, Biological Science Division, Pacific Northwest National Laboratory, Richland, WA 99352, United States
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Vilmos Kertesz
dBiosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, 37831 USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Neeraj Kumar
qComputational Biology Group, Biological Science Division, Pacific Northwest National Laboratory, Richland, WA 99352, United States
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Hyungro Lee
eDepartment of Electrical and Computer Engineering, Rutgers University, Piscataway, NJ 08854, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Zhuozhao Li
aData Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA
bDepartment of Computer Science, University of Chicago, Chicago, IL 60615, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Andre Merzky
eDepartment of Electrical and Computer Engineering, Rutgers University, Piscataway, NJ 08854, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Jurgen G. Schmidt
gBioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Li Tan
fComputational Sciences Initiative, Brookhaven National Laboratory, Upton, New York 11973, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Mikhail Titov
eDepartment of Electrical and Computer Engineering, Rutgers University, Piscataway, NJ 08854, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Anda Trifan
aData Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
nUniversity of Illinois at Urbana-Champaign, Champaign, IL 61820, USA
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Matteo Turilli
eDepartment of Electrical and Computer Engineering, Rutgers University, Piscataway, NJ 08854, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Hubertus Van Dam
fComputational Sciences Initiative, Brookhaven National Laboratory, Upton, New York 11973, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Srinivas C. Chennubhotla
pDepartment of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, 15260 USA
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Shantenu Jha
eDepartment of Electrical and Computer Engineering, Rutgers University, Piscataway, NJ 08854, USA
fComputational Sciences Initiative, Brookhaven National Laboratory, Upton, New York 11973, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Andrey Kovalevsky
cNeutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, TN, 37831, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Arvind Ramanathan
aData Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA
hConsortium for Advanced Science and Engineering, University of Chicago, Chicago, IL 60615, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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  • For correspondence: ramanathana@anl.gov
Marti Head
oJoint Institute for Biological Sciences, Oak Ridge National Laboratory, Oak Ridge, TN, 37831 USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Rick Stevens
bDepartment of Computer Science, University of Chicago, Chicago, IL 60615, USA
iComputing Environment and Life Sciences Directorate, Argonne National Laboratory, Lemont, IL 60439, USA
mNational Virtual Biotechnology Laboratory, US Department of Energy, Washington DC, USA
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Abstract

Despite the recent availability of vaccines against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the search for inhibitory therapeutic agents has assumed importance especially in the context of emerging new viral variants. In this paper, we describe the discovery of a novel non-covalent small-molecule inhibitor, MCULE-5948770040, that binds to and inhibits the SARS-Cov-2 main protease (Mpro) by employing a scalable high throughput virtual screening (HTVS) framework and a targeted compound library of over 6.5 million molecules that could be readily ordered and purchased. Our HTVS framework leverages the U.S. supercomputing infrastructure achieving nearly 91% resource utilization and nearly 126 million docking calculations per hour. Downstream biochemical assays validate this Mpro inhibitor with an inhibition constant (Ki) of 2.9 μ M [95% CI 2.2, 4.0]. Further, using room-temperature X-ray crystallography, we show that MCULE-5948770040 binds to a cleft in the primary binding site of Mpro forming stable hydrogen bond and hydrophobic interactions. We then used multiple μs-timescale molecular dynamics (MD) simulations, and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by Mpro, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits Mpro and offers a springboard for further therapeutic design.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://doi.org/10.6084/m9.figshare.13641101.v1

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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High Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Non-Covalent Inhibitor
Austin Clyde, Stephanie Galanie, Daniel W. Kneller, Heng Ma, Yadu Babuji, Ben Blaiszik, Alexander Brace, Thomas Brettin, Kyle Chard, Ryan Chard, Leighton Coates, Ian Foster, Darin Hauner, Vilmos Kertesz, Neeraj Kumar, Hyungro Lee, Zhuozhao Li, Andre Merzky, Jurgen G. Schmidt, Li Tan, Mikhail Titov, Anda Trifan, Matteo Turilli, Hubertus Van Dam, Srinivas C. Chennubhotla, Shantenu Jha, Andrey Kovalevsky, Arvind Ramanathan, Marti Head, Rick Stevens
bioRxiv 2021.03.27.437323; doi: https://doi.org/10.1101/2021.03.27.437323
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High Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Non-Covalent Inhibitor
Austin Clyde, Stephanie Galanie, Daniel W. Kneller, Heng Ma, Yadu Babuji, Ben Blaiszik, Alexander Brace, Thomas Brettin, Kyle Chard, Ryan Chard, Leighton Coates, Ian Foster, Darin Hauner, Vilmos Kertesz, Neeraj Kumar, Hyungro Lee, Zhuozhao Li, Andre Merzky, Jurgen G. Schmidt, Li Tan, Mikhail Titov, Anda Trifan, Matteo Turilli, Hubertus Van Dam, Srinivas C. Chennubhotla, Shantenu Jha, Andrey Kovalevsky, Arvind Ramanathan, Marti Head, Rick Stevens
bioRxiv 2021.03.27.437323; doi: https://doi.org/10.1101/2021.03.27.437323

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