期刊
FRONTIERS IN MOLECULAR BIOSCIENCES
卷 8, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fmolb.2021.666626
关键词
TMPRSS2 protein; molecular modeling; allosteric pocket; docking; MD simulation
资金
- Fondazione CARIPARO
The inhibitors camostat, nafamostat, and bromhexine target the transmembrane serine protease TMPRSS2 to prevent viral infections. Computational simulations reveal that binding of Ile256 induces a conformational change in the catalytic site of TMPRSS2, providing a rationale for enzyme activation. Furthermore, bromhexine competes with Ile256 for the binding site, suggesting its potential as an allosteric inhibitor of TMPRSS2.
Camostat, nafamostat, and bromhexine are inhibitors of the transmembrane serine protease TMPRSS2. The inhibition of TMPRSS2 has been shown to prevent the viral infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses. However, while camostat and nafamostat inhibit TMPRSS2 by forming a covalent adduct, the mode of action of bromhexine remains unclear. TMPRSS2 is autocatalytically activated from its inactive form, zymogen, through a proteolytic cleavage that promotes the binding of Ile256 to a putative allosteric pocket (A-pocket). Computer simulations, reported here, indicate that Ile256 binding induces a conformational change in the catalytic site, thus providing the atomistic rationale to the activation process of the enzyme. Furthermore, computational docking and molecular dynamics simulations indicate that bromhexine competes with the N-terminal Ile256 for the same binding site, making it a potential allosteric inhibitor. Taken together, these findings provide the atomistic basis for the development of more selective and potent TMPRSS2 inhibitors.
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