title: Drugs against avian influenza a virus: design of novel sulfonate inhibitors of neuraminidase N1.
abstract: The outbreak of avian influenza A (H5N1) virus has raised a global concern for both the animal as well as human health. Besides vaccination, that may not achieve full protection in certain groups of patients, inhibiting neuraminidase or the transmembrane protein M2 represents the main measure of controlling the disease. Due to alarming emergence of influenza virus strains resistant to the currently available drugs, development of new neuraminidase N1 inhibitors is of utmost importance. The present paper provides an overview of the recent advances in the design of new antiviral drugs against avian influenza. It also reports findings in binding free energy calculations for nine neuraminidase N1 inhibitors (oseltamivir, zanamivir, and peramivir -carboxylate, -phosphonate, and -sulfonate) using the Linear Interaction Energy method. Molecular dynamics simulations of these inhibitors were performed in a free and two bound states - the so called open and closed conformations of neuraminidase N1. Obtained results successfully reproduce the experimental binding affinities of the already known neuraminidase N1 inhibitors, i.e. peramivir being a stronger binder than zanamivir that is in turn stronger binder than oseltamivir, or phosphonate inhibitors being stronger binders than their carboxylate analogues. In addition, the newly proposed sulfonate inhibitors are predicted to be the strongest binders - a fact to be confirmed by their chemical synthesis and a subsequent test of their biological activity. Finally, contributions of individual inhibitor moieties to the overall binding affinity are explicitly evaluated to assist further drug development towards inhibition of the H5N1 avian influenza A virus.
authors.forename: Thanyarat
authors.initials: T
authors.lastname: Udommaneethanakit
authors.forename: Thanyada
authors.initials: T
authors.lastname: Rungrotmongkol
authors.forename: Vladimir
authors.initials: V
authors.lastname: Frecer
authors.forename: Pierfausto
authors.initials: P
authors.lastname: Seneci
authors.forename: Stanislav
authors.initials: S
authors.lastname: Miertus
authors.affiliation: Laboratory for Molecular Modeling, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia. bren@cmm.ki.si.
authors.forename: Urban
authors.initials: U
authors.lastname: Bren
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D001717:Birds / Q000821:virology; D015195:Drug Design; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000201:enzymology*; D005585:Influenza in Birds / Q000188:drug therapy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013451:Sulfonic Acids / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D013451:Sulfonic Acids; D009439:Neuraminidase