Withaniasomnifera phytochemicals possess SARS-CoV-2 RdRp and human TMPRSS2 protein binding potential

Coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has infected approximately 26 million people and caused more than 6 million deaths globally. Spike (S)-protein on the outer surface of the virus uses human trans-membrane serine protease-2 (TMPRSS2) to gain entry into the cell. Recent reports indicate that human dipeptidyl peptidase-4 inhibitors (DPP4 or CD26) could also be utilized to check the S-protein mediated viral entry into COVID-19 patients. RNA dependent RNA polymerase (RdRp) is another key virulence protein of SARS-CoV-2 life cycle. The study aimed to identify the potential anti-SARS-CoV-2 inhibitors present in Withania somnifera (Solanaceae) using computer aided drug discovery approach. Molecular docking results showed that flavone glycoside, sugar alcohol, and flavonoid present in W. somnifera showed − 11.69, − 11.61, − 10.1, − 7.71 kcal/mole binding potential against S-protein, CD26, RdRp, and TMPRSS2 proteins. The major standard inhibitors of the targeted proteins (Sitagliptin, VE607, Camostat mesylate, and Remdesivir) showed the − 7.181, − 6.6, − 5.146, and − 7.56 kcal/mole binding potential. Furthermore, the lead phytochemicals and standard inhibitors bound and non-bound RdRp and TMPRSS2 proteins were subjected to molecular dynamics (MD) simulation to study the complex stability and change in protein conformation. The result showed energetically favorable and stable complex formation in terms of RMSD, RMSF, SASA, Rg, and hydrogen bond formation. Drug likeness and physiochemical properties of the test compounds exhibited satisfactory results. Taken together, the present study suggests the presence of potential anti-SARS-CoV-2 phytochemicals in W. somnifera that requires further validation in in vitro and in vivo studies. Graphical Abstract