Impact of Remdesivir Incorporation along the Primer Strand on SARS-CoV-2 RNA-Dependent RNA Polymerase

Naseem-Khan, Sehr; Berger, Madison B.; Leddin, Emmett M.; Maghsoud, Yazdan; Cisneros, G. Andrés

doi:10.1021/acs.jcim.2c00201

Title: Impact of Remdesivir Incorporation along the Primer Strand on SARS-CoV-2 RNA-Dependent RNA Polymerase

Journal Article · 18 April 2022 · Journal of Chemical Information and Modeling

DOI: https://doi.org/10.1021/acs.jcim.2c00201 · OSTI ID:1981871

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^[1]; Maghsoud, Yazdan ^[2];

^[2]

University of North Texas, Denton, TX (United States)
University of North Texas, Denton, TX (United States); University of Texas at Dallas, Richardson, TX (United States)

Remdesivir was the first antiviral drug that received emergency use authorization from the United States Food and Drug Administration and is now formally approved 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 uses molecular dynamics simulations to explore the impact of remdesivir and two analogues as incoming nucleotides and of up to four incorporations of remdesivir along the primer strand on RdRp. The simulation results suggest that the overall structure and the dynamical behavior of RdRp are destabilized by remdesivir and the two analogues in the incoming position. The incorporation of remdesivir along the primer strand impacts specific non-bonded interactions between the nascent RNA and the polymerase subunit, as well as the overall dynamical networks on RdRp. The strongest impact on the structure and dynamics are observed after three incorporations, when remdesivir is located at position -A3, in agreement with previously reported experimental and computational results. Our results provide atomic-level details of the role played by remdesivir on the disruption of RNA synthesis by RdRp and the main drivers of these disruptions.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); University of North Texas, Denton, TX (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1981871

Journal Information:: Journal of Chemical Information and Modeling, Journal Name: Journal of Chemical Information and Modeling Journal Issue: 10 Vol. 62; ISSN 1549-9596

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Impact of Remdesivir Incorporation along the Primer Strand on SARS-CoV-2 RNA-Dependent RNA Polymerase

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