title: Source of oseltamivir resistance in avian influenza H5N1 virus with the H274Y mutation.
abstract: Molecular dynamics simulations were carried out for the mutant oseltamivir-NA complex, to provide detailed information on the oseltamivir-resistance resulting from the H274Y mutation in neuraminidase (NA) of avian influenza H5N1 viruses. In contrast with a previous proposal, the H274Y mutation does not prevent E276 and R224 from forming the hydrophobic pocket for the oseltamivir bulky group. Instead, reduction of the hydrophobicity and size of pocket in the area around an ethyl moiety at this bulky group were found to be the source of the oseltamivir-resistance. These changes were primarily due to the dramatic rotation of the hydrophilic -COO(-) group of E276 toward the ethyl moiety. In addition, hydrogen-bonding interactions with N1 residues at the -NH(3) (+) and -NHAc groups of oseltamivir were replaced by a water molecule. The calculated binding affinity of oseltamivir to NA was significantly reduced from -14.6 kcal mol(-1) in the wild-type to -9.9 kcal mol(-1) in the mutant-type.
authors.affiliation: Department of Chemistry, Faculty of Science, Chulalongkorn University, Patumwan, Bangkok, 10330, Thailand.
authors.forename: Maturos
authors.initials: M
authors.lastname: Malaisree
authors.forename: Thanyada
authors.initials: T
authors.lastname: Rungrotmongkol
authors.forename: Nadtanet
authors.initials: N
authors.lastname: Nunthaboot
authors.forename: Ornjira
authors.initials: O
authors.lastname: Aruksakunwong
authors.forename: Pathumwadee
authors.initials: P
authors.lastname: Intharathep
authors.forename: Panita
authors.initials: P
authors.lastname: Decha
authors.forename: Pornthep
authors.initials: P
authors.lastname: Sompornpisut
authors.forename: Supot
authors.initials: S
authors.lastname: Hannongbua
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D003461:Crystallography; D024882:Drug Resistance, Viral / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D053139:Oseltamivir / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D053139:Oseltamivir; D009439:Neuraminidase