The natural way forward: Molecular dynamics simulation analysis of phytochemicals from Indian medicinal plants as potential inhibitors of SARS-CoV-2 targets

The pandemic COVID-19 has become a global panic-forcing life towards a compromised "new normal." Antiviral therapy against SARS-CoV-2 is still lacking. Thus, development of natural inhibitors as a prophylactic measure is an attractive strategy. In this context, this work explored phytochemicals as potential inhibitors for SARS-CoV-2 by performing all atom molecular dynamics simulations using high performance computing for 8 rationally screened phytochemicals from Withania somnifera and Azadirachta indica and two repurposed drugs docked with the spike glycoprotein and the main protease of SARS-CoV-2. These phytochemicals were rationally screened from 55 Indian medicinal plants in our previous work. MM/PBSA, principal component analysis (PCA), dynamic cross correlation matrix (DCCM) plots and biological pathway enrichment analysis were performed to reveal the therapeutic efficacy of these phytochemicals. The results revealed that Withanolide R (-141.96 KJ/mol) and 2,3-Dihydrowithaferin A (-87.60 KJ/mol) were with the lowest relative free energy of binding for main protease and the spike proteins respectively. It was also observed that the phytochemicals exhibit a remarkable multipotency with the ability to modulate various human biological pathways especially pathways in cancer. Conclusively we suggest that these compounds need further detailed in vivo experimental evaluation and clinical validation to implement them as potent therapeutic agents for combating SARS-CoV-2.

Keywords: India; SARS-CoV-2; main protease; molecular dynamics; phytochemicals; relative free binding energy; simulation; spike.