Computational insights into the interactions of sofosbuvir and remdesivir with RNA-directed RNA polymerase: ligand screening, docking simulations, and interaction analysis

Abstract

This review explores sofosbuvir, a nucleoside analog approved for hepatitis C, as a potential inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), compared to remdesivir, which is constrained by hepatic and renal toxicity. RdRp, essential for viral replication, is a key target for COVID-19 therapeutics. Ligand-based virtual screening through the DrugRep virtual screening server, utilizing algorithms like Morgan fingerprint, identified compounds structurally akin to remdesivir. Structure-based molecular docking with CB-Dock2 and AutoDock Vina targeted the RdRp structure (PDB ID: 7BV2), revealing sofosbuvir’s binding affinity of − 7.6 kcal/mol, slightly lower than remdesivir’s − 8.4 kcal/mol, but with strong hydrogen bonds to ARG349 (3.05, 2.99, 2.89 Å) and CYS395 (3.41 Å), alongside Pi-Sigma and Pi-Alkyl interactions with PRO461 and VAL315. Molecular dynamics simulations (30 ns, LAMMPS) suggest sofosbuvir’s stability, with lower RMSD (~ 1.4 Å vs. ~ 1.8 Å for remdesivir) and more persistent hydrogen bonds, supported by its reliable structure and connectivity. Compared to remdesivir, sofosbuvir exhibits fewer unfavorable interactions and a well-established safety profile. Interaction analyses using BIOVIA Discovery Studio and LigPlot + confirmed sofosbuvir’s stability within the RdRp active site, corroborated by in vitro and clinical evidence. These findings highlight the pivotal role of in silico methods in drug repurposing for COVID-19. However, experimental validation is crucial to confirm sofosbuvir’s efficacy, particularly against SARS-CoV-2 variants, and to explore its therapeutic potential for addressing current and future viral threats.