In Silico Design of Natural Compound-Derived Novel Inhibitors Against RdRP OF SARS-CoV-2

RNA dependent RNA polymerase (RdRp), an important class of nucleic acid polymerases, encoded by RNA viruses such as SARS-CoV-2, has been a major drug target against viral diseases. Among the twenty-nine SARS-CoV-2 encoded proteins, RdRp is referred to as Non-Structural Protein 12 (Nsp12). Obtaining novel RdRp inhibitors is one of the crucial strategies in developing fast therapeutics against COVID-19. The NCI natural compound database containing 250 thousand small molecules was docked against the available 3D structure of SARS-CoV-2 RdRp (PDB ID: 7BV2). The molecules with best docking scores were assessed for their safety through ADMET predictions. Lead molecules that passed all the parameters of ADMET predictions, were subjected to molecular dynamic simulations and binding affinity analysis. This in silico study gave seven antiviral lead compounds that were having better binding affinities than the remdesivir. Their binding affinities ranged from −8.5 to −11.4 kcal/mol which is significantly higher than remdesivir (−7.59 kcal/mol). Besides, these novel antiviral compounds were found to bind between the Finger and Palm domains, restricting or obstructing the template RNA entry and movement, unlike remdesivir which binds at the 3’ end of the nascent RNA near the palm domain. The data indicates stable structures, favorable binding free energies when compared to remdesivir. Besides having better binding affinity, these leads have easy access to the binding pocket unlike the binding site of remdesivir that is in a deep cleft. These advantages of the identified novel compounds demand for immediate in vitro studies.