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

  • 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
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    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
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    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
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  • , 
  • 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
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  • , 
  • 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
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  • , 
  • 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
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    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
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  • , 
  • 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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  • , and 
  • 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
Cite this: J. Med. Chem. 2021, 64, 23, 17366–17383
Publication Date (Web):October 27, 2021
https://doi.org/10.1021/acs.jmedchem.1c01475
Copyright © 2021 American Chemical Society
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    Supporting Info (2)»
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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.

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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)

    • Molecular formula strings (CSV)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 17 publications.

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    2. Hongxiang Hu, Mohamed Dit Mady Traore, Ruiting Li, Hebao Yuan, Miao He, Bo Wen, Wei Gao, Colleen B. Jonsson, Elizabeth A. Fitzpatrick, Duxin Sun. Optimization of the Prodrug Moiety of Remdesivir to Improve Lung Exposure/Selectivity and Enhance Anti-SARS-CoV-2 Activity. Journal of Medicinal Chemistry 2022, 65 (18) , 12044-12054. https://doi.org/10.1021/acs.jmedchem.2c00758
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    12. Nashaat T. Nashed, Annie Aniana, Rodolfo Ghirlando, Sai Chaitanya Chiliveri, John M. Louis. Modulation of the monomer-dimer equilibrium and catalytic activity of SARS-CoV-2 main protease by a transition-state analog inhibitor. Communications Biology 2022, 5 (1) https://doi.org/10.1038/s42003-022-03084-7
    13. Nashaat T. Nashed, Daniel W. Kneller, Leighton Coates, Rodolfo Ghirlando, Annie Aniana, Andrey Kovalevsky, John M. Louis. Autoprocessing and oxyanion loop reorganization upon GC373 and nirmatrelvir binding of monomeric SARS-CoV-2 main protease catalytic domain. Communications Biology 2022, 5 (1) https://doi.org/10.1038/s42003-022-03910-y
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