ABSTRACT
Since December 2019, coronavirus disease (COVID-19) has claimed the lives of millions of people across the globe. To date, no medicine is available for the responsible virus SARS-CoV-2. 3CLpro, that is, 3-chymotrypsin-like protease, the main protease (Mpro ), has an important role in cleaving pp1a and pp1ab polyproteins. This Mpro serves as an important target in drug designing against COVID-19. Herein, the study includes the investigation, screening, and identification of potent leads from (Withania sps.), against SARS-CoV-2, using virtual screening, molecular docking, and molecular dynamics (MD) simulations. Seventy-three natural compounds from this important medicinal plant were screened. The Binding affinity was used to identify the most probable target to inhibit the Mpro , compounds 27-hydroxywithanolide F (W32, -11.5 kcal/mol), withanolide A (W56, -11.4 kcal/mol), and withacoagulin H (W30, -11.1 kcal/mol) showed highest binding energy. Lipinski's rule, followed by drug-likability and likeness screening, resulted in 36 molecules. Further, MD simulation of 50 ns predicted withacoagulin H possessing strong binding affinity and hydrogen-bonding interactions with the active site. The binding free energy calculation showed the most negative energy of withacoagulin H (-63.463 KJ/mol) compared to other selected compounds. The study also compared the bonding energy of already reported repurposed and newly synthesized drugs. Further, absorption, distribution, metabolism, and excretion predictions were made to found a good balance of potency. Hence the following screened compounds from Withania sps. could serve as the potential leads for drug development against COVID-19.