Virtual Screening of Natural Compounds as Potential SARS-CoV-2 M^pro Inhibitors: A Molecular Docking and Molecular Dynamics Simulation Guided Approach

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly impacted human lives, overburdened the healthcare system and weakened global economies. The lack of specific drugs against SARS-CoV-2 is a significant hurdle towards the successful treatment of COVID-19. The SARS-CoV-2 Main protease (M^pro) is considered an appealing target because of its role in replication in host cells. Plant-derived natural compounds are being largely tested for their efficacy against COVID-19 targets to combat SARS-CoV-2 infection. To discover hit compounds that can be used alone or in combination with repositioned drugs, we curated a set of 2,24,205 natural product structures from the ZINC database and virtually screened against covid-19 M^pro. The sequential docking protocols involving different level of exhaustiveness were performed to screen a library of natural compounds. Final 88 compounds were selected and post-processed using the MM-GBSA analysis for the generation of binding free energies. The top four compounds (ZINC000085626103, ZINC000085569275, ZINC000085625768 and ZINC000085488571) showing higher affinity against covid-19 M^pro enzyme selected for MD simulation studies. The RMSD, RMSF and RoG analysis of the all four compound-protein complexes indicated the absolute stability during 100ns MD run. Further the post-MD simulation binding free energies were calculated for all four compounds and were found to be in range of -38.29 to -18.07 kcal/mol. The In-silico virtual screening results suggested that the selected natural compounds have the potential to be developed as a COVID-19 M^pro inhibitor and can be explored further for experimental research to evaluate the in vitro and in vivo efficacy of these compounds for the treatment of COVID-19.