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Computational Identification of a Putative Allosteric Binding Pocket in TMPRSS2.
Jacopo Sgrignani1, Andrea Cavalli1,2
1Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Frontiers in Molecular Biosciences
|May 17, 2021
Summary
Bromhexine may act as an allosteric inhibitor of transmembrane serine protease TMPRSS2, potentially blocking viral entry. This finding offers a basis for developing new TMPRSS2 inhibitors for treating viral infections like SARS-CoV-2.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Biology
Background:
- Transmembrane serine protease TMPRSS2 is crucial for viral entry, including SARS-CoV-2.
- Camostat and nafamostat are known TMPRSS2 inhibitors, but bromhexine's mechanism is unclear.
Purpose of the Study:
- To elucidate the molecular mechanism of bromhexine's inhibition of TMPRSS2.
- To provide an atomistic basis for developing novel TMPRSS2 inhibitors.
Main Methods:
- Computer simulations (docking and molecular dynamics) were employed.
- The study focused on the allosteric activation mechanism of TMPRSS2.
Main Results:
- Ile256 binding to the A-pocket induces conformational changes in TMPRSS2's catalytic site.
- Bromhexine was computationally shown to compete with Ile256 for the A-pocket binding site.
- Bromhexine is proposed as a potential allosteric inhibitor of TMPRSS2.
Conclusions:
- The findings provide an atomistic understanding of TMPRSS2 activation and bromhexine's inhibitory potential.
- This research lays the groundwork for designing more selective and potent TMPRSS2 inhibitors.
- Understanding TMPRSS2 inhibition is vital for antiviral therapeutic development.
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