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

The main protease (Mpro or 3CLpro) 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 Mpro 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 Mpro enzyme. Based on the results, the structural and energetic features that explain why some drugs can be repositioned to inhibit Mpro from SARS-CoV-2 were exposed. These features should be considered for the design of novel Mpro inhibitors.