Microbial based natural compounds as potential inhibitors for SARS-CoV-2 Papain-like protease (PLpro): a molecular docking and dynamic simulation study.

COVID-19 (Coronavirus disease of 2019) pandemic is one of the largest health threats the planet has faced in recent decades. Efforts are being continuously made to design a viable drug or a vaccine. Several natural and synthetic molecules are under study for their potency to inhibit viral replication. In order to emphasize the importance of microbial-based natural components in antiviral drug discovery, an attempt has been made through this study to find potential inhibitors for SARS-CoV-2 Papain-Like protease (PLpro) molecule from microbial sources. PLpro, with its multifunctional roles like viral polypeptide proteolysis and suppression of the host's innate immune response, is acting as a potential drug target. The X-ray crystal structure of PLpro and ligand molecules were retrieved from the protein structure database and Npatlas database, respectively. The molecules were screened based on drug likeliness and the pharmacophore model created in reference to a known potent PLpro inhibitor GRL0617. Totally 3272 molecules have undergone the docking process and the complexes of top hits were subjected to 100 ns molecular dynamic simulation. The results showed that Holyrine B, Dihydroarcyriarubin C, Baraphenazine C and 3-hydroxy-3'-N-acetylholyrine A had formed a stable complex in the active site of the PLpro with significant interaction efficiency. Earlier studies showed that Holyrine B could also be a possible inhibitor of the Main protease of SARS-CoV-2, which increases its significance in the process of COVID-19 drug development. In conclusion, these microbial compounds can be considered as possible SARS-CoV-2 inhibitors for further in vitro studies. Communicated by Ramaswamy H. Sarma.