RESUMEN
RNA-dependent RNA polymerase, also known as RdRp, is a possible therapeutic target that could be used to suppress the proliferation of RNA viruses such as SARS-CoV-2. This protein has two major functional sites (a) catalytic and (b) substrate entry, which regulate the natural substrate entry and its corresponding interaction with the protein. In this study, a computational drug design pipeline was applied to investigate potential inhibitors against SARS-CoV-2 RdRp from Lauraceae plants, and five top hits were selected based on the docked score (< -7 kcal/mol). The docking study suggested that the Glochidioboside had a minimum binding score of -7.8 kcal/mol. This compound showed total five hydrogen bonds while two of them were with catalytic residues Asp618 and Asp760. However, another compound, Sitogluside showed a binding score of -7.3 kcal/mol with four hydrogen bonds targeting three functional residues (Arg555, Ser759, and Asp760). Later, 100 ns explicit solvent molecular dynamics (MD) simulation was performed to evaluate the stability of the protein-ligand docked system. These compounds translocated their positions from the catalytic site to the substrate entry site, as observed in the MD simulation trajectory. However, translocation did not affect the binding strength of these compounds, and they retained the strong binding affinity (ΔG < -11.5 kcal/mol), estimated using the MM/GBSA method. In general, the findings of this study indicated the potential therapeutic compounds that may be used targeting SARS-CoV-2 RdRp. However, these compounds still need to be validated by experimentation in order to determine their inhibitory function.Communicated by Ramaswamy H. Sarma.