title: Molecular basis of drug resistance in A/H1N1 virus.
abstract: New mutants of human influenza virus (A/H1N1) exhibit resistance to antiviral drugs. The mechanism whereby they develop insensitivity to these medications is, however, not yet completely understood. A crystallographic structure of A/H1N1 neuraminidase has been published recently. Using molecular dynamic simulations, it is now possible to characterize at the atomic level the mechanism that underlies the loss of binding affinity of the drugs. In this study, free-energy perturbation was used to evaluate the relative binding free energies of Tamiflu and Relenza with H274Y, N294S, and Y252H neuraminidase mutants. Our results demonstrate a remarkable correlation between theoretical and experimental data, which quantitatively confirms that the mutants are resistant to Tamiflu but are still strongly inhibited by Relenza. The simulations further reveal the key interactions that govern the affinity of the two drugs for each mutant. This information is envisioned to prove useful for the design of novel neuraminidase inhibitors and for the characterization of new potential mutants.
authors.affiliation: Center for Bioinformatics and Molecular Simulation, Universidad de Talca, Chile.
authors.forename: Ariela
authors.initials: A
authors.lastname: Vergara-Jaque
authors.forename: Horacio
authors.initials: H
authors.lastname: Poblete
authors.forename: Eric H
authors.initials: EH
authors.lastname: Lee
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
authors.forename: Fernando
authors.initials: F
authors.lastname: González-Nilo
authors.forename: Christophe
authors.initials: C
authors.lastname: Chipot
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000737:chemistry*; D003198:Computer Simulation; D024882:Drug Resistance, Viral / Q000235:genetics*; D006801:Humans; D006860:Hydrogen Bonding; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry / Q000201:enzymology / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D053139:Oseltamivir / Q000737:chemistry*; D055672:Static Electricity; D013816:Thermodynamics; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D053243:Zanamivir / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir