Molecular modelling on SARS-CoV-2 papain-like protease: an integrated study with homology modelling, molecular docking, and molecular dynamics simulations

SARS-CoV-2 PLpro was investigated as a therapeutic target for potent antiviral drugs due to its essential role in not only viral replication but also in regulating the inborn immune response. Several computational approaches, including homology modelling, molecular docking, and molecular dynamics (MD) studies, were employed to search for promising drugs in treating SARS-CoV-2. Eighty-one compounds, sub-structurally similar to the antiviral drug, were used as potential inhibitors of PLpro. From our results, three complexes containing the ligands with Pubchem IDs: 153012995, 12149203, and 123608715 showed lower binding ener- gies than the control (Ritonavir), indicating that they may become promising inhibitors for PLpro. MD was performed in a water sol-vent to validate the stability of the three complexes. All complexes achieved stable structure during the simulation as no significant fluctuations were observed in the validation parameters. Moreover, the binding energy for each complex was estimated using the MM- GBSA method. Complex 1 was the most stable structure based on the lowest binding energy score and its structure remained in a similar cavity with the docket snapshot. Based on our studies, three ligands were assumed to be potential inhibitors. The ligand of complex 1 may become the most promising antiviral drug against SARS-CoV-2 targeting PLpro.