Insight into the oseltamivir resistance R292K mutation in H5N1 influenza virus: a molecular docking and molecular
1Bioinformatics Division, School of Bio Sciences and Technology, VIT University, Vellore, 632014, Tamil Nadu, India.
Abstract:
H5N1 is a subtype of the influenza A virus that can cause disease in humans and many other animal species. Oseltamivir (Tamiflu) is a potent and selective antiviral drug employed to fight the flu virus in infected individuals by inhibiting neuraminidase (NA), a flu protein responsible for the release and spread of the progeny virions. However, oseltamivir resistance has become a critical problem. In particular, influenza strains with a R292K NA mutation are highly resistant to the oseltamivir. Though the biological functions of the mutations have previously been characterized, the structural basis behind the reduced catalytic activity and reduced protein level is not clear. In this study, molecular docking and molecular dynamics (MD) approach were employed to investigate the structural and dynamical effects throughout the protein structure and specifically, at the drug-binding pocket. Furthermore, potential of mean force was analyzed using explicit solvent MD simulations with the umbrella sampling method to explore the free energy of binding. It is believed that this study provides valuable guidance for the resistance management of oseltamivir and designing of more potent antiviral inhibitor.
Insights
Oseltamivir resistance in H5N1 influenza is linked to the R292K mutation. This study uses computational methods to reveal the structural basis for reduced drug effectiveness, aiding future antiviral design.
Area of Science:
- Virology
- Biochemistry
- Computational Biology
Background:
- H5N1 influenza poses a significant threat to human and animal health.
- Oseltamivir (Tamiflu) is a key antiviral, inhibiting influenza neuraminidase (NA).
- Oseltamivir resistance, particularly the R292K NA mutation, is a growing concern.
Purpose of the Study:
- To elucidate the structural and dynamical basis of oseltamivir resistance in H5N1 influenza.
- To understand the impact of the R292K NA mutation on enzyme activity and protein stability.
- To provide insights for developing novel antiviral inhibitors and managing drug resistance.
Main Methods:
- Molecular docking simulations to assess drug-target interactions.
- Molecular dynamics (MD) simulations to analyze protein structural and dynamic changes.
- Umbrella sampling with potential of mean force calculations to determine binding free energy.
Main Results:
- The R292K mutation significantly alters the drug-binding pocket structure and dynamics.
- Reduced catalytic activity and protein stability are associated with the R292K mutation.
- Computational analysis revealed key structural changes impacting oseltamivir binding affinity.
Conclusions:
- The study provides a detailed structural understanding of oseltamivir resistance mechanism.
- Findings guide the development of next-generation neuraminidase inhibitors.
- This research is crucial for effective influenza antiviral resistance management strategies.
More Related Videos
08:31Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
10:29Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
