Mutation-Induced Resistance of SARS-CoV-2 M^pro to WU-04 Revealed by Multi-Scale Modeling.

ABSTRACT: The clinical durability of SARS-CoV-2 main protease (M^pro) inhibitors depends on their resilience to emerging resistance mutations. Recent genomic surveillance and functional reports have highlighted substitutions at positions 49, 165, and 301, raising questions about the robustness of the noncovalent inhibitor WU-04 in variant backgrounds. Here, we combined μs-scale, triplicate molecular dynamics simulations with end-state binding free energy estimates and a network-rewiring inference (NRI) framework that maps long-range dynamical communication across the full protease dimer. We evaluated wild type (WT), single mutants M49K, M165V, S301P, and selected double mutants (M49K & M165V, M49K & S301P). Relative to WT, single substitutions produced reductions in computed binding affini

SUBMITTER: Liu M 

PROVIDER: S-EPMC12842141 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature