Title:Identifying TMPRSS2 Inhibitors by Drug Repurposing Screenings of
Known fXIa Inhibitors: A Computational Study
Volume: 21
Issue: 3
Author(s): Yanshu Liang*, Zhixia Qiao and Fancui Meng
Affiliation:
- School of Mechanical Engineering, Tianjin University of Commerce, Tianjin-300134, China
Keywords:
TMPRSS2, SARS-CoV-2, inhibitor, molecular docking, molecular dynamics, MM/GBSA.
Abstract:
Background: SARS-CoV-2 was reported to enter cells via binding to ACE2, followed by its
priming by TMPRSS2. Hence the inhibition of TMPRSS2 may block or decrease the severity of SARSCoV-
2, making TMPRSS2 an attractive target for COVID-19. fXIa has a similar binding pocket as
TMPRSS2, implying the possibility of fXIa inhibitors being TMPRSS2 inhibitors.
Methods: In order to find potential TMPRSS2 inhibitors, molecular docking of known fXIa inhibitors
was performed. Molecular dynamics simulations and MM/GBSA were conducted on representative compounds
with characteristic binding modes. R-group enumeration was used to generate compounds with
better binding interactions.
Results: Three scaffolds can make hydrogen bonds with Gly439 and Ser441, and form the chloride–
Tyr474 interactions at S1 pocket as well. Further structure optimization of one scaffold found that two
compounds have better docking scores and lower binding free energies.
Conclusion: Compounds R1a and R1b can be taken as potentially reversible inhibitors of TMPRSS2.
Our results could provide insight into both the discovery and lead optimization of TMPRSS2 inhibitors.
