SARS-CoV-2 is a single-stranded positive-sense RNA virus, and requires its RNA-dependent RNA polymerase (RdRP) to synthesize new viral RNA to propagate. Remdesivir is an adenosine-analogue, and a broad-spectrum antiviral that targets the viral RdRP. Remdesivir is thought to inhibit RNA synthesis through a delayed chain termination event, masking it from the viral exonuclease. We use molecular dynamics simulations to sample the translocation pathway of an incorporated Remdesivir at various positions on the primer strand, and calculate the free energies of the process as compared to a nascent base pair control. This shows in atomic detail how Remdesivir stalls the viral RdRP, and may aid in the development of more effective antivirals.

Free energy calculations of remdesivir in the SARS-CoV-2 RdRP provide a mechanism for its inhibition

ACS Fall 2021

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