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Updated: Jun 26, 2026
Detection of Neu1 Sialidase Activity in Regulating TOLL-like Receptor Activation
Published on: September 7, 2010
Molecular dynamics study on the effect of the N1 neuraminidase double mutant G147R/H274Y on oseltamivir sensitivity
Ardiana Ilham Nurrohman1,2, Hery Suwito3, Ni Nyoman Tri Puspaningsih2,3
1Bioinformatics Research Group, University-CoE-Research Center for Bio-Molecule Engineering (BIOME), Universitas Airlangga Surabaya 60115 Indonesia.
Abstract:
Inhibition of neuraminidase is the most prominent target in influenza medication using oseltamivir as an inhibitor. However, the emerging resistance of neuraminidase toward oseltamivir due to mutation reduces the efficacy of oseltamivir. The generally reported mutation is a single mutation at H274Y, which declines the sensitivity of oseltamivir by almost 900 folds compared to the wild-type variant. Moreover, an additional mutation at G147R increases the resistance by more than 2000 folds. However, sufficient studies on the resistance mechanism of this variant have not yet been reported. Therefore, we simulated four neuraminidase proteins comprising wild-type (WT), G147R, H274Y, and G147R/H274Y using molecular dynamics simulation to disclose the binding mechanism of oseltamivir. Trajectory analysis was conducted to reveal structural stability and flexibility. Furthermore, end-point free binding energy calculations were conducted. The energy decomposition of each residue was also calculated. The end-point energy calculation showed a similar result to that of experimental data. The energy decomposition analysis revealed that G147R/H274Y showed significant reduction in oseltamivir (OST) interaction with R118. Salt-bridge disruption caused by R224-E276 was also observed. Modification to enhance the polarity of the inhibitor might be useful in overcoming these changes. However, it should be noted that such changes could worsen the pharmacokinetic property of the inhibitor. It is hoped that these findings will provide useful insights for the development of an anti-influenza drug that can withstand the mutant variant.
Insights
Influenza drug resistance is increasing due to neuraminidase mutations like H274Y and G147R. Molecular simulations reveal how these mutations disrupt oseltamivir binding, aiding new drug development.
Area of Science:
- Biochemistry and Molecular Biology
- Pharmacology and Drug Discovery
- Computational Chemistry
Background:
- Neuraminidase inhibition is a key strategy for influenza treatment, with oseltamivir being a primary inhibitor.
- Emerging resistance mutations in neuraminidase, such as H274Y and G147R, significantly reduce oseltamivir efficacy.
- The precise resistance mechanisms of double mutations like G147R/H274Y remain incompletely understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying oseltamivir resistance in mutated neuraminidase variants.
- To elucidate the binding interactions of oseltamivir with wild-type and mutant neuraminidase proteins.
- To provide insights for developing novel anti-influenza drugs effective against resistant strains.
Main Methods:
- Molecular dynamics simulations were performed on four neuraminidase variants: wild-type (WT), G147R, H274Y, and G147R/H274Y.
- Analysis included trajectory analysis for structural stability and flexibility.
- End-point free binding energy calculations and residue-level energy decomposition were conducted.
Main Results:
- Binding energy calculations correlated well with experimental data.
- The G147R/H274Y double mutation significantly reduced oseltamivir interaction with residue R118.
- Disruption of the R224-E276 salt bridge was observed in the double mutant.
Conclusions:
- The G147R/H274Y mutation confers substantial resistance by altering key binding interactions.
- Modifying inhibitor polarity could potentially overcome resistance, but may impact pharmacokinetic properties.
- Findings offer valuable insights for designing next-generation anti-influenza agents effective against resistant variants.
