Abstract
The RNA-dependent RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a promising drug target for coronavirus disease 2019 (COVID-19) because it plays the most important role in the replication of the RNA genome. Nucleotide analogs such as remdesivir and favipiravir are thought to interfere with the RNA replication by RdRp. More specifically, they are expected to compete with nucleoside triphosphates, such as ATP. However, the process in which these drug molecules and nucleoside triphosphates are taken up by RdRp remains unknown. In this study, we performed all-atom molecular dynamics simulations to clarify the recognition mechanism of RdRp for these drug molecules and ATP that were at a distance. The ligand recognition ability of RdRp decreased in the order of remdesivir, favipiravir, and ATP. We also identified six recognition paths. Three of them were commonly found in all ligands, and the remaining three paths were ligand-dependent ones. In the common two paths, it was observed that the multiple lysine residues of RdRp carried the ligands to the binding site like a "bucket brigade." In the remaining common path, the ligands directly reached the binding site. Our findings contribute to the understanding of the efficient ligand recognition by RdRp at the atomic level.