Computational Identification of a Putative Allosteric Binding Pocket in TMPRSS2
Jacopo Sgrignani, Andrea Cavalli
Frontiers in Molecular Biosciences, doi:10.3389/fmolb.2021.666626
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 (Apocket). 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.
AUTHOR CONTRIBUTIONS JS designed the study, performed and analyzed simulations and experiments, and wrote and revised the manuscript. AC designed the study, analyzed the results of simulations and experiments, and wrote and revised the manuscript. Both authors contributed to the article and approved the submitted version.
SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmolb. 2021.666626/full#supplementary-material
Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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