title: Novel neuraminidase inhibitors: identification, biological evaluation and investigations of the binding mode.
abstract: BACKGROUND
  The pathogenicity of influenza A and B viruses depends on the function of influenza neuraminidase (NA). Emerging resistant influenza A viruses of subtype H1N1 increasingly challenge the effectiveness of established NA inhibitors. Recent computational studies have indicated several weak points of NA that can be exploited for rational inhibitor design to conquer this imminent threat, such as the opening of the binding pocket due to the flexibility of the 150-, 245- and 430-loops.
  
  
  METHODS
  We employed shape-focused virtual screening based on a recently discovered lead compound, katsumadain A, to identify novel promising compounds with significant inhibitory efficacy on NA and resistance-breaking capacity on oseltamivir-resistant strains. A potential binding mode of these compounds was derived employing ligand-based techniques and protein-ligand docking using representative protein conformations selected from molecular dynamics simulations.
  
  
  RESULTS
  Five novel compounds were identified by virtual screening. Their IC(50) values, determined in chemiluminescence-based NA inhibition assays, are in the range of 0.18-17 µM. In particular, artocarpin exhibits high affinity toward three H1N1 oseltamivir-sensitive influenza A viruses. It also inhibits the NA of an oseltamivir-resistant H1N1 isolate.
authors: Institute of Theoretical Chemistry and Center for Molecular Biosciences, University of Innsbruck, Austria.
authors: Johannes
authors: J
authors: Kirchmair
authors: Judith M
authors: JM
authors: Rollinger
authors: Klaus R
authors: KR
authors: Liedl
authors: Nora
authors: N
authors: Seidel
authors: Andi
authors: A
authors: Krumbholz
authors: Michaela
authors: M
authors: Schmidtke
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000633:toxicity; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology; D009980:Influenza A virus / Q000201:enzymology; D009981:Influenza B virus / Q000201:enzymology; D056004:Molecular Dynamics Simulation; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053139:Oseltamivir / Q000737:chemistry / Q000633:toxicity; D011485:Protein Binding
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D053139:Oseltamivir; D009439:Neuraminidase