Binding roles of major components and new inhibitor from Andrographis paniculata targeting SARS-CoV-2 main protease using molecular dynamics simulations, density functional theory, and in vitro study.

In a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the main protease Mpro plays a crucial role in the viral replication process. Andrographis paniculata has been reported for anti-SARS-CoV-2 properties. This work aims to identify new SARS-CoV-2 Mpro inhibitors and investigate the binding roles of major diterpene lactones derived from Andrographis paniculata. Molecular docking and molecular dynamic (MD) simulations with the dimeric SARS-CoV-2 Mpro were performed to identify the potential compounds which are five major diterpene lactones and four selected compounds. Binding affinities, expressed as binding and interaction energies, were calculated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method and the quantum mechanics/molecular mechanics (QM/MM) using density functional theory. Principal component analysis (PCA), along with free energy landscape (FEL) analysis, was performed to assess the stability of the ligand-protein binding interactions. The density functional theory in terms of residual interaction energies revealed that H-bond, H-pi and pi-pi interactions were key interactions during the binding. Andrographidine E from Andrographis paniculata was found to be a new SARS-CoV-2 Mpro inhibitor with the IC50 of 158 μM. The results help explain the roles of binding of compounds against dimeric SARS-CoV-2Mpro which will be useful for the development of SARS-CoV-2 Mpro inhibitors.