Impact of Remdesivir Incorporation Along the Primer Strand on SARS-CoV-2 RNA-dependent RNA polymerase

Remdesivir was the first antiviral drug that received emergency use authorization from the United States Food and Drug Administration to treat COVID-19. Remdesivir is a nucleotide analogue that targets the RNA-dependent RNA polymerase (RdRp) of coronaviruses, including SARS-CoV-2. The solution of multiple RdRp structures has been one of the main axes of research in the race against the SARS-CoV-2 virus. Several hypotheses of the mechanism of inhibition of RdRp by remdesivir have been proposed, although open questions remain. This work explores the impact of up to four incorporations of remdesivir along the primer strand on RdRp by means of molecular dynamics (MD) simulations. The simulation results suggest that the overall structure and dynamical behavior of RdRp is destabilized by remdesivir. The strongest impact on the structure and dynamics are observed after three incorporations, when remdesivir is located at position -A3. Our results are consistent with previously reported experimental and computational results, and help provide further atomic-level detail on the role played by remdesivir on the disruption of RNA synthesis by RdRp.