Structure-based Virtual Screening and Molecular Dynamic Simulation Studies of the Natural Inhibitors of SARS-CoV-2 Main Protease

In the month of December 2019, the outbreak of COVID-19 disease in China marked the beginning of a global health challenge and the urgent need to discover and design appropriate therapeutic agents. The causative agent, SARS-CoV-2 has a high rate of infectivity and its Main protease enzyme plays a major role in the replication mechanism of the virus.  This study is aimed at prospecting for natural compounds that have strong binding affinity and the ability to inhibit the SARS-CoV-2 Main Protease. A library of 1,048 natural compounds (with zero violations for Lipinski and Veber rules) obtained from edible African plants were used for this study. These compounds were molecularly docked against the SARS-CoV-2 Main Protease and the results were screened with the docking score obtained from N3 (-7.8 kcal/mol), which is a co-crystallized ligand of the target protein. Further screening for molar refractivity, pharmacokinetic properties and bioactivity was done with SWISSADME, pKCSM, and Molinspiration webservers respectively. The binding site analyses were done using the PLIP and Fpocket webservers. Molecular dynamic studies and analyses of Apo and Holo structures of target protein were done with the Galaxy webserver. The lead compounds, Rhamnetin and Ellagic acid show better therapeutic prediction than the standard. Whilst Rhamnetin binds at the active site, Ellagic acid binds at another cavity with a probable allosteric effect as suggested by the molecular dynamic studies. Further tests are required to evaluate the SARS-CoV-2 Main protease inhibition properties of the lead compounds.