title: Exploring the cause of oseltamivir resistance against mutant H274Y neuraminidase by molecular simulation approach.
abstract: Oseltamivir (Tamiflu) is the preferred anti-viral drug employed to fight the flu virus in infected individuals. The principal target for this drug is a virus surface glycoprotein, neuraminidase (NA), which facilitates the release of nascent virus and thus spreads infections. Until recently, only a low prevalence of neuraminidase inhibitors (NAIs) resistance (<1%) had been detected in circulating viruses. However, there have been reports of significant numbers of A (H1N1) influenza strains with a H274Y neuraminidase mutation that was highly resistant to the NAI, oseltamivir. In this study, we highlight the effect of point mutation-induced oseltamivir resistance in H1N1 subtype neuraminidases by molecular docking and molecular dynamics simulation approach. Our results suggested that wild-type NA could be more indispensable for the oseltamivir binding, as characterized by minimum number of H-bonds, high flexibility and largest binding affinity than mutant-type NA. This study throws light on the possible effects of drug-resistant mutations on the large functionally important collective motions in biological systems.
authors.affiliation: Bioinformatics Division, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014 Tamil Nadu, India.
authors.forename: V
authors.initials: V
authors.lastname: Karthick
authors.forename: V
authors.initials: V
authors.lastname: Shanthi
authors.forename: R
authors.initials: R
authors.lastname: Rajasekaran
authors.forename: K
authors.initials: K
authors.lastname: Ramanathan
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D007251:Influenza, Human / Q000821:virology*; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D053139:Oseltamivir / Q000494:pharmacology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D053139:Oseltamivir; C487630:NA protein, influenza A virus; D009439:Neuraminidase