title: How does each substituent functional group of oseltamivir lose its activity against virulent H5N1 influenza mutants?
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.
authors.affiliation: Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Thanyada
authors.initials: T
authors.lastname: Rungrotmongkol
authors.forename: Thanyarat
authors.initials: T
authors.lastname: Udommaneethanakit
authors.forename: Maturos
authors.initials: M
authors.lastname: Malaisree
authors.forename: Nadtanet
authors.initials: N
authors.lastname: Nunthaboot
authors.forename: Pathumwadee
authors.initials: P
authors.lastname: Intharathep
authors.forename: Pornthep
authors.initials: P
authors.lastname: Sompornpisut
authors.forename: Supot
authors.initials: S
authors.lastname: Hannongbua
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000235:genetics; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D008968:Molecular Conformation / Q000187:drug effects; D009154:Mutation; D053139:Oseltamivir / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014774:Virulence / Q000187:drug effects* / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir