Identification of potential natural product inhibitors against the Mpro enzyme of Covid-19: a computational study

The main protease (M^pro), also called 3C-like protease, activates the initial step of Covid-19 replication by the proteolytic cleavage of viral polyprotein. The M^pro of Covid-19 is distinctly different from the proteases of the host cell (human), which makes M^pro an attractive therapeutic target for small molecule inhibitors. Herein, we have employed extensive computational approaches to identify a novel chemical scaffold against the M^pro enzyme of Covid-19. The pharmacophore model was developed and then validated by Gunner–Henry method. The validated model was then used for the virtual screening. The identified natural product compounds revealed good docking score and interactions with receptor. The final candidate hit established hydrogen bond interactions with essential binding pocket residues of the M^pro enzyme. Moreover, several hydrophobic interactions were also observed between the final candidate hit compound and the M^pro enzyme. Molecular dynamics simulation confirmed the stability of the identified hits in complex with M^pro enzyme. Finally, we argue that this study will potentially contribute to expand the chemical space of M^pro enzyme inhibition and could potentially develop new safe and efficient natural drugs against the Covid-19.