Drug repurposing and computational modeling for discovery of inhibitors of the main protease (M pro ) of SARS-CoV-2.

The main protease (M pro or 3CL pro ) is a conserved cysteine protease from the coronaviruses and started to be considered an important drug target for developing antivirals, as it produced a deadly outbreak of COVID-19. Herein, we used a combination of drug reposition and computational modeling approaches including molecular docking, molecular dynamics (MD) simulations, and the calculated binding free energy to evaluate a set of drugs in complex with the M pro enzyme. Particularly, our results show that darunavir and triptorelin drugs have favorable binding free energy (-63.70 and -77.28 kcal mol -1 , respectively) in complex with the M pro enzyme. Based on the results, the structural and energetic features that explain why some drugs can be repositioned to inhibit M pro from SARS-CoV-2 were exposed. These features should be considered for the design of novel M pro inhibitors.