title: In silico analysis of drug-resistant mutant of neuraminidase (N294S) against oseltamivir.
abstract: The recent H1N1 influenza pandemic has attracted worldwide attention due to the high infection rate. Oseltamivir is a new class of anti-viral agent approved for the treatment and prevention of influenza infections. The principal target for this drug is a virus surface glycoprotein, neuraminidase (NA), which facilitates the release of nascent virus and thus spreads infection. Until recently, only a low prevalence of neuraminidase inhibitor (NAI) resistance (<1 %) had been detected in circulating viruses. However, there have been reports of significant numbers of A (H1N1) influenza strains with a N294S neuraminidase mutation that was highly resistant to the NAI, oseltamivir. Hence, in the present study, we highlight the effect of point mutation-induced oseltamivir resistance in H1N1 subtype neuraminidases by molecular simulation approach. The docking analysis reveals that mutation (N294S) significantly affects the binding affinity of oseltamivir with mutant type NA. This is mainly due to the decrease in the flexibility of binding site residues and the difference in prevalence of hydrogen bonds in the wild and mutant structures. 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: D001665:Binding Sites; D003198:Computer Simulation; D024882:Drug Resistance, Viral; D006860:Hydrogen Bonding; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009439:Neuraminidase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D053139:Oseltamivir / Q000737:chemistry* / Q000494:pharmacology*; D017354:Point Mutation; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D053139:Oseltamivir; D009439:Neuraminidase