title: Molecular prediction of oseltamivir efficiency against probable influenza A (H1N1-2009) mutants: molecular modeling approach.
abstract: To predict the susceptibility of the probable 2009 influenza A (H1N1-2009) mutant strains to oseltamivir, MD/LIE approach was applied to oseltamivir complexed with the most frequent drug-resistant strains of neuraminidase subtypes N1 and N2: two mutations on the framework residues (N294S and H274Y) and the two others on the direct-binding residues (E119V and R292K) of oseltamivir. Relative to those of the wild type (WT), loss of drug-target interaction energies, especially in terms of electrostatic contributions and hydrogen bonds were dominantly established in the E119V and R292K mutated systems. The inhibitory potencies of oseltamivir towards the WT and mutants were predicted according to the ordering of binding-free energies: WT (-12.3 kcal mol(-1)) > N294S (-10.4 kcal mol(-1)) > H274Y (-9.8 kcal mol(-1)) > E119 V (-9.3 kcal mol(-1)) > R292K (-7.7 kcal mol(-1)), suggesting that the H1N1-2009 influenza with R292K substitution, perhaps, conferred a high level of oseltamivir resistance, while the other mutants revealed moderate resistance levels. This result calls for an urgent need to develop new potent anti-influenza agents against the next pandemic of potentially higher oseltamivir-resistant H1N1-2009 influenza.
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: Maturos
authors.initials: M
authors.lastname: Malaisree
authors.forename: Nadtanet
authors.initials: N
authors.lastname: Nunthaboot
authors.forename: Pornthep
authors.initials: P
authors.lastname: Sompornpisut
authors.forename: Supot
authors.initials: S
authors.lastname: Hannongbua
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D003198:Computer Simulation; D024882:Drug Resistance, Viral / Q000235:genetics*; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D053139:Oseltamivir / Q000378:metabolism / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir