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    Proton-Coupled Conformational Activation of SARS Coronavirus Main Proteases and Opportunity for Designing Small-Molecule Broad-Spectrum Targeted Covalent Inhibitors.

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    Author
    Verma, Neha
    Henderson, Jack A
    Shen, Jana
    Date
    2020-12-15
    Journal
    Journal of the American Chemical Society
    Publisher
    American Chemical Society
    Type
    Article
    Other
    
    Metadata
    Show full item record
    See at
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754784/
    Abstract
    The SARS coronavirus 2 (SARS-CoV-2) main protease (Mpro) is an attractive broad-spectrum antiviral drug target. Despite the enormous progress in structure elucidation, the Mpro's structure-function relationship remains poorly understood. Recently, a peptidomimetic inhibitor has entered clinical trial; however, small-molecule orally available antiviral drugs have yet to be developed. Intrigued by a long-standing controversy regarding the existence of an inactive state, we explored the proton-coupled dynamics of the Mpros of SARS-CoV-2 and the closely related SARS-CoV using a newly developed continuous constant pH molecular dynamics (MD) method and microsecond fixed-charge all-atom MD simulations. Our data supports a general base mechanism for Mpro's proteolytic function. The simulations revealed that protonation of His172 alters a conserved interaction network that upholds the oxyanion loop, leading to a partial collapse of the conserved S1 pocket, consistent with the first and controversial crystal structure of SARS-CoV Mpro determined at pH 6. Interestingly, a natural flavonoid binds SARS-CoV-2 Mpro in the close proximity to a conserved cysteine (Cys44), which is hyper-reactive according to the CpHMD titration. This finding offers an exciting new opportunity for small-molecule targeted covalent inhibitor design. Our work represents a first step toward the mechanistic understanding of the proton-coupled structure-dynamics-function relationship of CoV Mpros; the proposed strategy of designing small-molecule covalent inhibitors may help accelerate the development of orally available broad-spectrum antiviral drugs to stop the current pandemic and prevent future outbreaks.
    Keyword
    Mpro
    broad-spectrum antiviral drug target
    small-molecule
    inhibitors
    SARS-CoV-2
    Antiviral Agents
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/14352
    ae974a485f413a2113503eed53cd6c53
    10.1021/jacs.0c10770
    Scopus Count
    Collections
    UMB Coronavirus Publications
    UMB Open Access Articles 2020

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