Proton-Coupled Conformational Activation of SARS Coronavirus Main Proteases and Opportunity for Designing Small-Molecule Broad-Spectrum Targeted Covalent Inhibitors.
dc.contributor.author | Verma, Neha | |
dc.contributor.author | Henderson, Jack A | |
dc.contributor.author | Shen, Jana | |
dc.date.accessioned | 2021-01-13T19:04:10Z | |
dc.date.available | 2021-01-13T19:04:10Z | |
dc.date.issued | 2020-12-15 | |
dc.identifier.uri | http://hdl.handle.net/10713/14352 | |
dc.description.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. | en_US |
dc.description.uri | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754784/ | en_US |
dc.language.iso | en | en_US |
dc.publisher | American Chemical Society | en_US |
dc.relation.ispartof | Journal of the American Chemical Society | en_US |
dc.subject | Mpro | en_US |
dc.subject | broad-spectrum antiviral drug target | en_US |
dc.subject | small-molecule | en_US |
dc.subject | inhibitors | en_US |
dc.subject.mesh | SARS-CoV-2 | en_US |
dc.subject.mesh | Antiviral Agents | en_US |
dc.title | Proton-Coupled Conformational Activation of SARS Coronavirus Main Proteases and Opportunity for Designing Small-Molecule Broad-Spectrum Targeted Covalent Inhibitors. | en_US |
dc.type | Article | en_US |
dc.type | Other | en_US |
dc.identifier.doi | 10.1021/jacs.0c10770 | |
dc.identifier.pmid | 33320670 | |
dc.source.volume | 142 | |
dc.source.issue | 52 | |
dc.source.beginpage | 21883 | |
dc.source.endpage | 21890 | |
dc.source.country | United States | |
dc.source.country | United States |
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UMB Coronavirus Publications
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UMB Open Access Articles 2020