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Structural, Electronic, and Electrostatic Determinants for Inhibitor Binding to Subsites S1 and S2 in SARS-CoV-2 Main Protease

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    Structural, Electronic, and Electrostatic Determinants for Inhibitor Binding to Subsites S1 and S2 in SARS-CoV-2 Main Protease
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    • Daniel W. Kneller
      Daniel W. Kneller
      Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      More by Daniel W. Kneller
      Orcidhttps://orcid.org/0000-0002-5416-5789
    • Hui Li
      Hui Li
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      More by Hui Li
      Orcidhttps://orcid.org/0000-0002-6964-9962
    • Stephanie Galanie
      Stephanie Galanie
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      More by Stephanie Galanie
    • Gwyndalyn Phillips
      Gwyndalyn Phillips
      Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      More by Gwyndalyn Phillips
    • Audrey Labbé
      Audrey Labbé
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      More by Audrey Labbé
    • Kevin L. Weiss
      Kevin L. Weiss
      Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      More by Kevin L. Weiss
      Orcidhttps://orcid.org/0000-0002-6486-8007
    • Qiu Zhang
      Qiu Zhang
      Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      More by Qiu Zhang
    • Mark A. Arnould
      Mark A. Arnould
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
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    • Austin Clyde
      Austin Clyde
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      Data Science and Learning Division, Argonne National Laboratory, Lemont, Illinois 60439, United States
      Department of Computer Science, University of Chicago, Chicago, Illinois 60615, United States
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    • Heng Ma
      Heng Ma
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      Data Science and Learning Division, Argonne National Laboratory, Lemont, Illinois 60439, United States
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    • Arvind Ramanathan
      Arvind Ramanathan
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      Data Science and Learning Division, Argonne National Laboratory, Lemont, Illinois 60439, United States
      Consortium for Advanced Science and Engineering, University of Chicago, Chicago, Illinois 60615, United States
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      Orcidhttps://orcid.org/0000-0002-1622-5488
    • Colleen B. Jonsson
      Colleen B. Jonsson
      Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
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      Orcidhttps://orcid.org/0000-0002-2640-7672
    • Martha S. Head
      Martha S. Head
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      Joint Institute for Biological Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
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    • Leighton Coates
      Leighton Coates
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      Second Target Station, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
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      Orcidhttps://orcid.org/0000-0003-2342-049X
    • John M. Louis
      John M. Louis
      Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland 20892-0520, United States
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    • Peter V. Bonnesen*
      Peter V. Bonnesen
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      *Email: [email protected]
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    • Andrey Kovalevsky*
      Andrey Kovalevsky
      Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
      National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States
      *Email: [email protected]
      More by Andrey Kovalevsky
      Orcidhttps://orcid.org/0000-0003-4459-9142
    Other Access OptionsSupporting Information (2)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 23, 17366–17383
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.1c01475
    Published October 27, 2021
    Copyright © 2021 American Chemical Society
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    Abstract

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    Creating small-molecule antivirals specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins is crucial to battle coronavirus disease 2019 (COVID-19). SARS-CoV-2 main protease (Mpro) is an established drug target for the design of protease inhibitors. We performed a structure–activity relationship (SAR) study of noncovalent compounds that bind in the enzyme’s substrate-binding subsites S1 and S2, revealing structural, electronic, and electrostatic determinants of these sites. The study was guided by the X-ray/neutron structure of Mpro complexed with Mcule-5948770040 (compound 1), in which protonation states were directly visualized. Virtual reality-assisted structure analysis and small-molecule building were employed to generate analogues of 1. In vitro enzyme inhibition assays and room-temperature X-ray structures demonstrated the effect of chemical modifications on Mpro inhibition, showing that (1) maintaining correct geometry of an inhibitor’s P1 group is essential to preserve the hydrogen bond with the protonated His163; (2) a positively charged linker is preferred; and (3) subsite S2 prefers nonbulky modestly electronegative groups.

    Copyright © 2021 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01475.

    • Crystallographic data collection and refinement statistics for the joint X-ray/neutron structure of SARS-CoV-2 Mpro in complex with compound 1 (Table S1); data reduction and refinement statistics for the room temperature X-ray crystal structures of SARS-CoV-2 Mpro-inhibitor complexes used in this study (Table S2); superpositions of Mpro-1 with Mpro ligand-free and Mpro-telaprevir neutron structures (Figure S1); cytotoxicity and antiviral activity of the selected molecules against SARS-CoV-2 (Figure S2); binding isotherms for the interaction of compound 1 and its analogues with Mpro (Figure S3); electron density for ligands from room temperature X-ray co-crystal structures (Figure S4); superpositions of Mpro-1 X-ray/neutron structure with selected HL-3 complex structures (Figure S5); RMSD of MD simulation trajectories (Figure S6); crystals of Mpro-inhibitor complexes used (Figure S7); pre-mounted crystal of ∼2.1 mm3 dMpro-1 complex used for neutron diffraction and subsequent X-ray data collection (Figure S8); materials and methods, 1H and 13C NMR spectra, and mass spectra (PDF)

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    Cited By

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    This article is cited by 35 publications.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 23, 17366–17383
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.1c01475
    Published October 27, 2021
    Copyright © 2021 American Chemical Society
    Request reuse permissions

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