Design and discovery of some novel protease inhibitors against SARS-CoV-2 main protease by molecular docking, drug-likeness and ADME studies: An in-silico approach:

Abstract

SARS-CoV-2 emerges as a new curse to the life of global population. The infectivity and spreading rate of the disease makes it a pandemic with no such specific drug discovered yet. Considering the high spreading rate of the disease, there is an urgent need of selective anti-SARS-CoV-2 agent. SARS-CoV-2 main protease is an important target involved in transcription of the viral RNA, inhibition of which may lead to virucidal action. Repurposing strategy proves some antivirals to be effective against Mpro, but safety issues are of concern. To identify lead, computational approaches are the best to consider. The present study incorporates three standard anti-HIV agents Lopinavir, Ritonavir and Indinavir to undergo pharmacophore modeling. The initial modeling resulted in the selection of few test compounds considering the low RMSD as observed in Zinc database. Rest of the compounds was designed from the pharmacophoric features of the newly developed model. 20 compounds were subjected to molecular docking. The docking results showed that, compound 20 revealed the highest binding energy (-8.6 kcal/mol), which is even lesser than all the three standards. The other compounds 3, 4, 5, 11 and 19 also responded well to the docking study. These six compounds were further evaluated for their drug-likeness and ADME properties to raise the acceptance level of the lead(s). Further computational study includes the Molecular-Dynamic simulation of the compound 20, to ensure no or lesser variations throughout the simulation analysis. The above sequential computational study provides a hypothetical guideline to optimize the lead as effective anti-SARS-CoV-2 agent.