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dc.contributor.authorVerma, Neha
dc.contributor.authorHenderson, Jack A
dc.contributor.authorShen, Jana
dc.date.accessioned2021-01-13T19:04:10Z
dc.date.available2021-01-13T19:04:10Z
dc.date.issued2020-12-15
dc.identifier.urihttp://hdl.handle.net/10713/14352
dc.description.abstractThe 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.urihttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754784/en_US
dc.language.isoenen_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.ispartofJournal of the American Chemical Societyen_US
dc.subjectMproen_US
dc.subjectbroad-spectrum antiviral drug targeten_US
dc.subjectsmall-moleculeen_US
dc.subjectinhibitorsen_US
dc.subject.meshSARS-CoV-2en_US
dc.subject.meshAntiviral Agentsen_US
dc.titleProton-Coupled Conformational Activation of SARS Coronavirus Main Proteases and Opportunity for Designing Small-Molecule Broad-Spectrum Targeted Covalent Inhibitors.en_US
dc.typeArticleen_US
dc.typeOtheren_US
dc.identifier.doi10.1021/jacs.0c10770
dc.identifier.pmid33320670
dc.source.volume142
dc.source.issue52
dc.source.beginpage21883
dc.source.endpage21890
dc.source.countryUnited States
dc.source.countryUnited States


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