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 (Mpro) 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 Mpro, 17 were
chosen for evaluation in a kinetic assay for Mpro inhibition.
Remarkably 14 of the compounds at 100-μM concentration were
found to reduce the enzymatic activity and 5 provided IC50 values below 40 μM: manidipine (4.8 μM), boceprevir
(5.4 μM), lercanidipine (16.2 μM), bedaquiline (18.7 μM),
and efonidipine (38.5 μM). Structural analyses reveal a common
cloverleaf pattern for the binding of the active compounds to the
P1, P1′, and P2 pockets of Mpro. 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.