Computational assessment of select antiviral phytochemicals as potential SARS-Cov-2 main protease inhibitors: molecular dynamics guided ensemble docking and extended molecular dynamics

Covid-19 caused by novel coronavirus, 2019-nCoV or SARS-CoV-2 has become most severe pandemic of this century. No specific therapies are available to treat Covid-19 so far. Recently, main protease (M(pro)), a potential drug target from SARS-CoV-2 has been successfully crystallised. The present study is aimed at assessment of bioactive antiviral phytochemicals as potential SARS-COV-2 M(pro) inhibitors, using ensemble docking, molecular dynamics and MM-PBSA calculations. Ensemble docking studies were performed with Autodock vina program. The top 5 compounds having highest binding free energy were subjected to 100 ns molecular dynamics simulations with Gromacs. The resulting trajectories of converged period of MD were further exploited in MM-PBSA calculations to derive accurate estimates of binding free energies. The MD results were analysed with respect to RMSD, RMSF and hydrogen bond formation and occupancy parameters. The drugs remdesivir and nelfinavir were used as standard drugs for comparative studies. In the docking studies five phytochemicals, dalpanitin, amentoflavone, naringin, hinokiflavone, and rutin were found having lowest binding free energies (< − 10 kcal mol(−1)) which is lower than standard drugs. MD studies suggested that the complexes of these five phytochemicals with M(pro) stabilize with well accepted RMSD. Amongst these phytochemicals, hinokiflavove, amentoflavone and naringin were found having better binding affinity with ΔG(binging) than the standard drug remdesivir. Investigations and validation of these inhibitors against SARS-CoV-2 would be helpful in bring these molecules at the clinical settings. [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00107-9.