title: Screening from the world's largest TCM database against H1N1 virus.
abstract: The swine influenza virus (H1N1) 2009 pandemic highlights the importance of having effective anti-viral strategies. Recently, oseltamivir (Tamiflu) resistant influenza viruses are identified; which further emphasizes the urgency in developing new antiviral agents. In influenza virus replication cycle, viral surface glycoprotein, hemagglutinin, is responsible for viral entry into host cells. Hence, a potentially effective antiviral strategy is to inhibit viral entry mechanism. To develop novel antiviral agent that inhibits viral entry, we analyzed 20,000 traditional Chinese medicine (TCM) ingredients in hemagglutinin subtype H1 sialic acid binding site found on H1N1 virus. We then performed molecular dynamics simulations to investigate receptor-ligand interaction of the candidates obtained from docking. Here, we report three TCM derivatives that have high binding affinities to H1 sialic acid binding site residues based on structure-based calculations. The top three derivatives, xylopine_2, rosmaricine_14 and rosmaricine_15, all have an amine group that interact with Glu83 and a pyridinium group that interact with Asp103. Molecular dynamics simulations show that these derivatives form strong hydrogen bonding with Glu83 but interact transiently with Asp103. We therefore suggest that an enhanced hemagglutinin inhibitor, based on our scaffold, should be designed to bind both Glu83 and Asp103 with high affinity.
authors.affiliation: Laboratory of Computational and Systems Biology, School of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan.
authors.forename: Tung-Ti
authors.initials: TT
authors.lastname: Chang
authors.forename: Mao-Feng
authors.initials: MF
authors.lastname: Sun
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chen
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Mark
authors.initials: M
authors.lastname: Fisher
authors.forename: Jaung-Geng
authors.initials: JG
authors.lastname: Lin
authors.forename: Calvin Yu-Chian
authors.initials: CY
authors.lastname: Chen
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D006388:Hemagglutinins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry* / Q000378:metabolism; D008516:Medicine, Chinese Traditional; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D016415:Sequence Alignment
chemical_list: D000998:Antiviral Agents; D006388:Hemagglutinins; D019158:N-Acetylneuraminic Acid; D000117:Acetylglucosamine