Identification Of 14 Known Drugs As Inhibitors Of The Main Protease Of Sars-Cov-2

A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibitors of the main protease (M-pro) of SARS-CoV-2, the virus responsible for COVID-19. 42 drugs emerged as top candidates, and after visual analyses of the predicted structures of their complexes with M-pro, 17 were chosen for evaluation in a kinetic assay for M-pro inhibition. Remarkably 14 of the compounds at 100-mu M concentration were found to reduce the enzymatic activity and 5 provided IC50 values below 40 mu M: manidipine (4.8 mu M), boceprevir (5.4 mu M), lercanidipine (16.2 mu M), bedaquiline (18.7 mu M), and efonidipine (38.5 EM). Structural analyses reveal a common cloverleaf pattern for the binding of the active compounds to the P1, P1', and P2 pockets of M-pro. Further study of the most active compounds in the context of COVID-19 therapy is warranted, while all of the active compounds may provide a foundation for lead optimization to deliver valuable chemotherapeutics to combat the pandemic.