Non-covalent TMPRSS2 inhibitors identified from virtual screening

Hu, Xin; Shrimp, Jonathan H.; Guo, Hui; Zakharov, Alexey; Jain, Sankalp; Shinn, Paul; Simeonov, Anton; Hall, Matthew D.; Shen, Min

The SARS-CoV-2 pandemic has prompted researchers to pivot their efforts to finding antiviral compounds and vaccines. In this study, we focused on the human host cell transmembrane protease serine 2 (TMPRSS2), which plays an important role in the viral life cycle by cleaving the spike protein to initiate membrane fusion. TMPRSS2 is an attractive target and has received significant attention for the development of drugs against SARS and MERS. Starting with comparative structural modeling and binding model analysis, we developed an efficient pharmacophore-based approach and applied in a large-scale in silico database screening for small molecule inhibitors against TMPRSS2. A number of novel inhibitors were identified, providing starting points for further development of drug candidates for the treatment of COVID-19.