Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation.

In the rapidly evolving coronavirus disease (COVID-19) pandemic, repurposing existing drugs and evaluating commercially available inhibitors against druggable targets of the virus could be an effective strategy to accelerate the drug discovery process. The 3C-Like proteinase (3CLpro) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as an important drug target due to its role in viral replication. The lack of a potent 3CLpro inhibitor and the availability of the X-ray crystal structure of 3CLpro (PDB-ID 6LU7) motivated us to perform computational studies to identify commercially available potential inhibitors. A combination of modeling studies was performed to identify potential 3CLpro inhibitors from the protease inhibitor database MEROPS ( https://www.ebi.ac.uk/merops/index.shtml ). Binding energy evaluation identified key residues for inhibitor design. We found 15 potential 3CLpro inhibitors with higher binding affinity than that of an α-ketoamide inhibitor determined via X-ray structure. Among them, saquinavir and three other investigational drugs aclarubicin, TMC-310911, and faldaprevir could be suggested as potential 3CLpro inhibitors. We recommend further experimental investigation of these compounds.