Binding Mechanism of the Active Form of Molnupiravir to RdRp of SARS-CoV-2 and Designing Potential Analogues: Insights from Molecular Dynamics Simulations.

ABSTRACT: Molnupiravir, an FDA-approved nucleoside prodrug for treating COVID-19, converts into N4-hydroxycytidine triphosphate (NHC-TP), which integrates into SARS-CoV-2 RNA by its RNA-dependent RNA polymerase (RdRp) causing lethal mutations in viral proteins. Due to the risk of RdRp-mediated drug resistance and potential off-target effects on host polymerases (e.g., human polymerase II/HPolII), it is crucial to understand NHC-TP interactions at polymerase active sites for developing new, resistance-proof treatments. In this study, we used molecular dynamics (MD) simulations to probe key interactions between NHC-TP and SARS-CoV-2 RdRp and designed novel NHC-TP analogues with greater selectivity for SARS-CoV-2 RdRp over HPolII by a virtual screening workflow. We docked NHC-TP to a modified SARS-CoV-

SUBMITTER: Carbone J 

PROVIDER: S-EPMC11465654 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature