Identifying TMPRSS2 Inhibitors by Drug Repurposing Screenings of Known fXIa Inhibitors: A Computational Study

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 SARS-CoV-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.