Structural modeling and analysis of the SARS-CoV-2 cell entry inhibitor camostat bound to the trypsin-like protease TMPRSS2.

ABSTRACT: The type II transmembrane serine protease TMPRSS2 facilitates the entry of coronaviruses, such as SARS-CoV-2, into host cells by cleaving the S₁/S₂ interface of the viral spike protein. Based on structural data derived from X-ray crystallographic data of related trypsin-like proteases, a homology model of TMPRSS2 is described and validated using the broad spectrum COVID-19 drug candidate camostat as a probe. Both active site recognition and catalytic function are examined using quantum mechanics/molecular mechanics molecular dynamic (QM/MM MD) simulations of camostat and its active metabolite, 4-(4-guanidinobenzoyloxy) phenylacetate (GBPA). Substrate binding is shown to be primarily stabilized through salt bridge formation between the shared guanidino pharmacophore an

SUBMITTER: Escalante DE 

PROVIDER: S-EPMC7862521 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature