Investigation of the inhibitory activity of some dietary bioactive flavonoids against SARS-CoV-2 using molecular dynamics simulations and MM-PBSA calculations

Eventhough the development of vaccine against COVID-19 pandemic is progressing in different part of the world a well-defined treatment plan is not yet developed. Therefore, we investigate the inhibitory activity of a group of dietary bioactive flavonoids against SARS-CoV-2 main protease (M^pro), which are identified as one of the potential targets in the drug discovery process of COVID-19. After the initial virtual screening of a number of bioactive flavonoids, the binding affinity of three compounds - Naringin, Naringenin and Amentoflavone - at the active site of M^pro was investigated through MD Simulations, MM-PBSA and DFT Binding Energy calculations. From the MD trajectory analysis, Amentoflavone and Naringin showed consistent protein-ligand interactions with the aminoacid residues of the active site domains of M^pro. The excellent inhibitory activity of Amentoflavone and Naringin was established from its MM-PBSA binding energy values of -190.50 and -129.87 kJ/mol respectively. The MET165 residue of M^pro is identified as one of the key residue which contributed significantly to MM-PBSA binding energy through hydrophobic interactions. Furthermore, the DFT binding energy values of Amentoflavone (-182.92 kJ/mol) and Naringin (-160.67 kJ/mol) in active site molecular clusters with hydrogen bonds confirmed their potential inhibitory activity. These compounds are of high interest because of their wide availability, low cost, no side effects, and long history of use. We can prevent the severity of this disease for home care patients using these effective dietary supplements. We are hopeful that our results have implications for the development of prophylaxis of COVID-19.Communicated by Ramaswamy H. Sarma.