A computational study on the molecular mechanisms of panduratin A as a potential inhibitor on SARS-CoV-2 protein targets.

ABSTRACT

Panduratin A from Boesebergia rotunda was recently reported as a potent anti-SARS-CoV-2 compound. However, the molecular mechanisms underlying the inhibition by Panduratin A and its target remained unclear. Molecular docking calculations were performed between panduratin A and five important proteins, i.e., main protease (Mpro), papain-like protease (PLpro), receptor binding domain (RBD) of spike proteins, RNA-dependent-RNA-polymerase (RdRp), and 2'-O-methyltransferase (MTase). The estimated binding free energy and the interaction networks extracted from the best docking mode for each complex suggested that MTase was the most probable target for panduratin A inhibition. To further validate the ability of panduratin A to inhibit MTase, molecular dynamics (MD) simulations and binding free energy calculations were performed for panduratin A-MTase complex, in comparison with another MTase complex with sinefungin as a positive control. Chemical features of panduratin A and sinefungin were compared for their contribution in MTase binding. It was found that both molecules could bind to the S-Adenosyl methionine (SAM) binding pocket and prevent the SAM entrance co-substrate, which could eventually halt the function of MTase. Despite a slightly weaker binding free energy, the equilibrated positional binding of panduratin A was found at a closer distance to the active sites. Therefore, this study proposed MTase as a possible target of panduratin A, along with the mechanisms of inhibition, prompting another future in vitro study as a verification.