Computational Identification of a Putative Allosteric Binding Pocket in TMPRSS2
Sgrignani et al.,
Computational Identification of a Putative Allosteric Binding Pocket in TMPRSS2,
Frontiers in Molecular Biosciences, doi:10.3389/fmolb.2021.666626
In Silico study of TMPRSS2 inhibition by camostat, nafamostat, and bromhexine, suggesting allosteric binding for bromhexine, compared to camostat and nafamostat which bind to the active site of TMPRSS2 forming covalent adducts.
Sgrignani et al., 30 Apr 2021, peer-reviewed, 2 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: ORIGINAL RESEARCH
published: 30 April 2021
doi: 10.3389/fmolb.2021.666626
Computational Identification of a
Putative Allosteric Binding Pocket in
TMPRSS2
Jacopo Sgrignani 1* and Andrea Cavalli 1,2*
1
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland, 2 Swiss Institute
of Bioinformatics, Lausanne, Switzerland
Edited by:
Massimiliano Bonomi,
Institut Pasteur, France
Reviewed by:
Therese E. Malliavin,
Institut Pasteur, France
Matteo Masetti,
University of Bologna, Italy
*Correspondence:
Jacopo Sgrignani
jacopo.sgrignani@irb.usi.ch
Andrea Cavalli
andrea.cavalli@irb.usi.ch
Specialty section:
This article was submitted to
Biological Modeling and Simulation,
a section of the journal
Frontiers in Molecular Biosciences
Received: 10 February 2021
Accepted: 01 April 2021
Published: 30 April 2021
Citation:
Sgrignani J and Cavalli A (2021)
Computational Identification of a
Putative Allosteric Binding Pocket
in TMPRSS2.
Front. Mol. Biosci. 8:666626.
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.
Keywords: TMPRSS2 protein, molecular modeling, allosteric pocket, docking, MD simulation
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