Dynamical fragment molecular orbital interaction analysis of SARS-CoV-2 RNA-dependent RNA polymerase and remdesivir

Remdesivir was developed as a nucleoside analog inhibitor targeting the RNA-dependent RNA polymerase (RdRp) of the Ebola virus. It was shown to be an effective treatment for coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir is incorporated into the RdRp of SARS-CoV-2, and it becomes inactivated when remdesivir comes to the −3 position by adding three nucleotides behind. However, the detailed molecular mechanism of its inactivation remains unknown. In this study, we performed a dynamical interaction analysis combining classical molecular dynamics (MD) simulations and fragment molecular orbital (FMO) calculations on the structures of RdRp and RNA complexes with remdesivir at four different positions. The results showed that the interaction between remdesivir at position −3 and Lys593 has significant importance in inhibiting RNA elongation of RdRp. Therefore, the combination of MD and FMO calculations a useful method to clarify the molecular recognition mechanism in the biological environment.