COVID-19, a pandemic caused by the virus SARS-CoV-2, has spread globally, necessitating the search for
antiviral compounds. Transmembrane
protease serine 2 (TMPRSS2) is a cell surface
protease that plays an essential role in
SARS-CoV-2 infection. Therefore, researchers are searching for TMPRSS2 inhibitors that can be used for the treatment of
COVID-19. As such, in this study, based on the crystal structure, we targeted the active site of TMPRSS2 for virtual screening of compounds in the FDA database. Then, we screened
lumacaftor and
ergotamine, which showed strong binding ability, using 100 ns molecular dynamics simulations to study the stability of the
protein-
ligand binding process, the flexibility of
amino acid residues, and the formation of hydrogen bonds. Subsequently, we calculated the binding free energy of the
protein-
ligand complex by the MM-
PBSA method. The results show that
lumacaftor and
ergotamine interact with residues around the TMPRSS2 active site, and reached equilibrium in the 100 ns molecular dynamics simulations. We think that
lumacaftor and
ergotamine, which we screened through in silico studies, can effectively inhibit the activity of TMPRSS2. Our findings provide a basis for subsequent in vitro experiments, having important implications for the development of effective anti-COVID-19 drugs.