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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2021, 64, 8, 4991-5000
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Direct Observation of Protonation State Modulation in SARS-CoV-2 Main Protease upon Inhibitor Binding with Neutron Crystallography

  • Daniel W. Kneller
    Daniel W. Kneller
    Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37831, United States
    National Virtual Biotechnology Laboratory, US Department of Energy, Washington, D.C. 20585, United States
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    • , 
  • Gwyndalyn Phillips
    Gwyndalyn Phillips
    Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37831, United States
    National Virtual Biotechnology Laboratory, US Department of Energy, Washington, D.C. 20585, United States
    More by Gwyndalyn Phillips
    • , 
  • Kevin L. Weiss
    Kevin L. Weiss
    Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37831, United States
    National Virtual Biotechnology Laboratory, US Department of Energy, Washington, D.C. 20585, United States
    More by Kevin L. Weiss
    Orcidhttp://orcid.org/0000-0002-6486-8007
    • , 
  • Qiu Zhang
    Qiu Zhang
    Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37831, United States
    National Virtual Biotechnology Laboratory, US Department of Energy, Washington, D.C. 20585, United States
    More by Qiu Zhang
    • , 
  • Leighton Coates*
    Leighton Coates
    National Virtual Biotechnology Laboratory, US Department of Energy, Washington, D.C. 20585, United States
    Second Target Station, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37831, United States
    *Email: [email protected]
    More by Leighton Coates
    Orcidhttp://orcid.org/0000-0003-2342-049X
    • , and 
  • Andrey Kovalevsky*
    Andrey Kovalevsky
    Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37831, United States
    National Virtual Biotechnology Laboratory, US Department of Energy, Washington, D.C. 20585, United States
    *Email: [email protected]
    More by Andrey Kovalevsky
    Orcidhttp://orcid.org/0000-0003-4459-9142
Cite this: J. Med. Chem. 2021, 64, 8, 4991–5000
Publication Date (Web):March 23, 2021
https://doi.org/10.1021/acs.jmedchem.1c00058
Not subject to U.S. Copyright. Published 2021 by American Chemical Society
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ACS AuthorChoiceACS AuthorChoiceCC: Creative CommonsCC: Creative CommonsBY: Credit must be given to the creatorBY: Credit must be given to the creatorNC: Only noncommercial uses of the work are permittedNC: Only noncommercial uses of the work are permittedND: No derivatives or adaptations of the work are permittedND: No derivatives or adaptations of the work are permitted
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Supporting Info (1)»
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Abstract

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The main protease (3CL Mpro) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. To date, no small-molecule clinical drugs are available that specifically inhibit SARS-CoV-2 Mpro. To aid rational drug design, we determined a neutron structure of Mpro in complex with the α-ketoamide inhibitor telaprevir at near-physiological (22 °C) temperature. We directly observed protonation states in the inhibitor complex and compared them with those in the ligand-free Mpro, revealing modulation of the active-site protonation states upon telaprevir binding. We suggest that binding of other α-ketoamide covalent inhibitors can lead to the same protonation state changes in the Mpro active site. Thus, by studying the protonation state changes induced by inhibitors, we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 Mpro.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00058.

  • Neutron and X-ray data collection statistics; photo of 0.5 mm3 crystal of SARS-CoV-2 Mpro–telaprevir complex; superposition of Mpro–telaprevir neutron structure with the neutron structure of ligand-free Mpro (PDB ID 7JUN); and superposition of Mpro–telaprevir neutron structure with the X-ray structure of Mpro in complex with inhibitor 13b (PDB ID 6Y2F) (PDF)

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