title: Designing inhibitors of M2 proton channel against H1N1 swine influenza virus.
abstract: BACKGROUND
  M2 proton channel of H1N1 influenza A virus is the target protein of anti-flu drugs amantadine and rimantadine. However, the two once powerful adamantane-based drugs lost their 90% bioactivity because of mutations of virus in recent twenty years. The NMR structure of the M2 channel protein determined by Schnell and Chou (Nature, 2008, 451, 591-595) may help people to solve the drug-resistant problem and develop more powerful new drugs against H1N1 influenza virus.
  
  
  METHODS
  Docking calculation is performed to build the complex structure between receptor M2 proton channel and ligands, including existing drugs amantadine and rimantadine, and two newly designed inhibitors. The computer-aided drug design methods are used to calculate the binding free energies, with the computational biology techniques to analyze the interactions between M2 proton channel and adamantine-based inhibitors.
  
  
  CONCLUSIONS
  1) The NMR structure of M2 proton channel provides a reliable structural basis for rational drug design against influenza virus. 2) The channel gating mechanism and the inhibiting mechanism of M2 proton channel, revealed by the NMR structure of M2 proton channel, provides the new ideas for channel inhibitor design. 3) The newly designed adamantane-based inhibitors based on the modeled structure of H1N1-M2 proton channel have two pharmacophore groups, which act like a "barrel hoop", holding two adjacent helices of the H1N1-M2 tetramer through the two pharmacophore groups outside the channel. 4) The inhibitors with such binding mechanism may overcome the drug resistance problem of influenza A virus to the adamantane-based drugs.
authors.affiliation: Guangxi Academy of Sciences, Nanning, Guangxi, China. qishi_du@yahoo.com.cn
authors.forename: Qi-Shi
authors.initials: QS
authors.lastname: Du
authors.forename: Ri-Bo
authors.initials: RB
authors.lastname: Huang
authors.forename: Shu-Qing
authors.initials: SQ
authors.lastname: Wang
authors.forename: Kuo-Chen
authors.initials: KC
authors.lastname: Chou
mesh_terms: D000218:Adamantane / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000235:genetics; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009154:Mutation; D009976:Orthomyxoviridae Infections / Q000662:veterinary / Q000821:virology; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012299:Rimantadine / Q000737:chemistry / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D013552:Swine; D013553:Swine Diseases / Q000821:virology; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D000086082:Viroporin Proteins
chemical_list: D000218:Adamantane; D000998:Antiviral Agents; D007473:Ion Channels; D012299:Rimantadine; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins