Screening potential FDA-approved inhibitors of the SARS-CoV-2 major protease 3CLpro through high-throughput virtual screening and molecular dynamics simulation

It has been confirmed that the new coronavirus SARS-CoV-2 caused the global pandemic of coronavirus disease 2019 (COVID-19). Studies have found that 3-chymotrypsin-like protease (3CL(pro)) is an essential enzyme for virus replication, and could be used as a potential target to inhibit SARS-CoV-2. In this work, 3CL(pro) was used as the target to complete the high-throughput virtual screening of the FDA-approved drugs, and Indinavir and other 10 drugs with high docking scores for 3CLpro were obtained. Studies on the binding pattern of 3CL(pro) and Indinavir found that Indinavir could form the stable hydrogen bond (H-bond) interactions with the catalytic dyad residues His41-Cys145. Binding free energy study found that Indinavir had high binding affinity with 3CL(pro). Subsequently, molecular dynamics simulations were performed on the 3CL(pro) and 3CL(pro)-Indinavir systems, respectively. The post-dynamic analyses showed that the conformational state of the 3CLpro-Indinavir system transformed significantly and the system tended to be more stable. Moreover, analyses of the residue interaction network (RIN) and H-bond occupancy revealed that the residue-residue interaction at the catalytic site of 3CL(pro) was significantly enhanced after binding with Indinavir, which in turn inactivated the protein. In short, through this research, we hope to provide more valuable clues against COVID-19.