Development of new inhibitor candidates for Sars-Cov-2 3CLpro (Main Protease): A molecular docking and molecular dynamics simulation study

Despite the normalization in the human mobility worldwide caused by COVID-19 pandemics, the disease still remains as a major threat with emerge of new variants and therefore it is a popular target for the drug development. The 3CLpro is one of the most pivotal targets of SARS-CoV-2 which is needed for the cleavage of viral polyproteins into nonstructural proteins that are essential for viral replication. A total of 756958 molecules from ZINC15 database have been screened against 3CLpro by molecular docking. The docking scores of the top 100 ligands were in the range of −82.25 kcal/mol and −98.06 kcal/mol. Top scored nine ligands and co-crystalized N3 were forwarded to the MD simulations and binding free energy studies. The binding free energy values of ligands and N3 were in the range of −22.04 kcal/mol and −105.01 kcal/mol. Moreover, the binding free energy results of newly studied ligands were better than N3 ligand. In addition, the docking and the MD results indicated that ligands have valuable interactions with 3CLpro binding site key residues, such as His41, Cys145 and Glu166. The ligand H03 demonstrated better results than all studied ligands as well than N3 for both of docking and binding free energy calculations.