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Volume 27
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10.3390/ijms27021000
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Mutation-Induced Resistance of SARS-CoV-2 Mpro to WU-04 Revealed by Multi-Scale Modeling

by
Mengting Liu
1,2,3,4,
Derui Zhao
2,3,
Hui Duan
2,3,
Junyao Zhu
2,3,
Liting Zheng
2,3,
Nan Yuan
2,3,
Yuanling Xia
5,
Peng Sang
2,3,4,* and
Liquan Yang
2,3,4,*
1
College of Pharmacy, Dali University, Dali 671003, China
2
College of Agriculture and Biological Science, Dali University, Dali 671003, China
3
Key Laboratory of Bioinformatics and Computational Biology, Department of Education of Yunnan Province, Dali University, Dali 671003, China
4
Co-Innovation Center for Cangshan Mountain and Erhai Lake Integrated Protection and Green Development of Yunnan Province, Dali University, Dali 671003, China
5
State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Science, Yunnan University, Kunming 650091, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(2), 1000; https://doi.org/10.3390/ijms27021000 (registering DOI)
Submission received: 29 October 2025 / Revised: 13 January 2026 / Accepted: 16 January 2026 / Published: 19 January 2026
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Versions Notes

Abstract

The clinical durability of SARS-CoV-2 main protease (Mpro) 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 affinity of up to ~12kcal/mol, accompanied by loss or reshaping of the S2 subsite and altered ligand burial. Notably, the M49K/S301P double mutant partially restored WU-04 engagement, narrowing the ΔΔGrestore gap to within ΔΔGrestore of WT and re-establishing key hydrophobic and hydrogen-bond contacts. NRI analysis revealed that distal residue 301 participates in a communication corridor linking the C-terminal helical domain to the active-site cleft; its substitution rewires inter-domain coupling that can compensate for local disruptions at residue 49. Together, these results identify structural hotspots and network pathways that may inform the design of next-generation Mpro inhibitors with improved mutation tolerance—specifically by strengthening interactions that do not rely solely on the mutable S2 pocket and by engaging conserved backbone features near the 165–166 region.
Keywords: noncovalent inhibitor; neural relational inference (NRI) model; protein-inhibitor interaction network; drug resistance mutations; WU-04 noncovalent inhibitor; neural relational inference (NRI) model; protein-inhibitor interaction network; drug resistance mutations; WU-04

Share and Cite

MDPI and ACS Style

Liu, M.; Zhao, D.; Duan, H.; Zhu, J.; Zheng, L.; Yuan, N.; Xia, Y.; Sang, P.; Yang, L. Mutation-Induced Resistance of SARS-CoV-2 Mpro to WU-04 Revealed by Multi-Scale Modeling. Int. J. Mol. Sci. 2026, 27, 1000. https://doi.org/10.3390/ijms27021000

AMA Style

Liu M, Zhao D, Duan H, Zhu J, Zheng L, Yuan N, Xia Y, Sang P, Yang L. Mutation-Induced Resistance of SARS-CoV-2 Mpro to WU-04 Revealed by Multi-Scale Modeling. International Journal of Molecular Sciences. 2026; 27(2):1000. https://doi.org/10.3390/ijms27021000

Chicago/Turabian Style

Liu, Mengting, Derui Zhao, Hui Duan, Junyao Zhu, Liting Zheng, Nan Yuan, Yuanling Xia, Peng Sang, and Liquan Yang. 2026. "Mutation-Induced Resistance of SARS-CoV-2 Mpro to WU-04 Revealed by Multi-Scale Modeling" International Journal of Molecular Sciences 27, no. 2: 1000. https://doi.org/10.3390/ijms27021000

APA Style

Liu, M., Zhao, D., Duan, H., Zhu, J., Zheng, L., Yuan, N., Xia, Y., Sang, P., & Yang, L. (2026). Mutation-Induced Resistance of SARS-CoV-2 Mpro to WU-04 Revealed by Multi-Scale Modeling. International Journal of Molecular Sciences, 27(2), 1000. https://doi.org/10.3390/ijms27021000

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