How does each substituent functional group of oseltamivir lose its activity against virulent H5N1 influenza mutants?
Thanyada Rungrotmongkol1, Thanyarat Udommaneethanakit, Maturos Malaisree
1Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Abstract:
To reveal the source of oseltamivir-resistance in influenza (A/H5N1) mutants, the drug-target interactions at each functional group were investigated using MD/LIE simulations. Oseltamivir in the H274Y mutation primarily loses the electrostatic and the vdW interaction energies at the -NH(3)(+) and -OCHEt(2) moieties corresponding to the weakened hydrogen-bonds and changed distances to N1 residues. Differentially, the N294S mutation showed small changes of binding energies and intermolecular interactions. Interestingly, the presence of different conformations of E276 positioned between the -OCHEt(2) group and the mutated residue is likely to play an important role in oseltamivir-resistant identification. In the H274Y mutant, it moves towards the -OCHEt(2) group leading to a reduction in hydrophobicity and pocket size, whilst in the N294S mutant it acts as the hydrogen network center bridging with R224 and the mutated residue S294. The molecular details have answered a question of how the H274Y and N294S mutations confer the high- and medium-level of oseltamivir-resistance to H5N1.
Insights
Oseltamivir resistance in H5N1 influenza arises from specific mutations. Molecular simulations reveal how H274Y and N294S mutations alter drug-target interactions, impacting neuraminidase inhibitor efficacy.
Area of Science:
- Virology
- Computational Biology
- Drug Discovery
Background:
- Influenza A (H5N1) poses a significant pandemic threat.
- Neuraminidase inhibitors like oseltamivir are crucial for treatment.
- Emergence of drug-resistant strains necessitates understanding resistance mechanisms.
Purpose of the Study:
- To elucidate the molecular basis of oseltamivir resistance in H5N1 influenza.
- To investigate the impact of specific mutations (H274Y, N294S) on drug-target interactions.
- To identify key residues and conformational changes conferring resistance.
Main Methods:
- Molecular Dynamics (MD) and Linear Interaction Energy (LIE) simulations were employed.
- Analysis of drug-target interactions at functional group levels.
- Investigation of electrostatic, van der Waals energies, hydrogen bonds, and residue conformations.
Main Results:
- The H274Y mutation significantly weakens electrostatic and van der Waals interactions of oseltamivir, primarily due to altered hydrogen bonds and distances to N1 residues.
- The N294S mutation shows minimal changes in binding energies and intermolecular interactions.
- Conformational changes in E276 play a critical role, influencing hydrophobicity and pocket size in H274Y, and acting as a hydrogen bond center in N294S.
Conclusions:
- H274Y mutation confers high-level oseltamivir resistance by disrupting key drug-binding interactions.
- N294S mutation confers medium-level resistance through subtle alterations in binding and E276 conformation.
- Molecular insights into these resistance mechanisms are vital for developing effective antiviral strategies against H5N1 influenza.
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