title: Antiviral potential and molecular insight into neuraminidase inhibiting diarylheptanoids from Alpinia katsumadai.
abstract: At present, neuraminidase (NA) inhibitors are the mainstay of pharmacological strategies to fight against global pandemic influenza. In the search for new antiviral drug leads from nature, the seed extract of Alpinia katsumadai has been phytochemically investigated. Among the six isolated constituents, four diarylheptanoids showed in vitro NA inhibitory activities in low micromolar ranges against human influenza virus A/PR/8/34 of subtype H1N1. The most promising constituent, katsumadain A (4; IC(50) = 1.05 +/- 0.42 microM), also inhibited the NA of four H1N1 swine influenza viruses, with IC(50) values between 0.9 and 1.64 muM, and showed antiviral effects in plaque reduction assays. Considering the flexible loop regions of NA, extensive molecular dynamics (MD) simulations were performed to study the putative binding mechanism of the T-shaped diarylheptanoid 4. Docking results showed well-established interactions between the protein and the core of this novel NA-inhibiting natural scaffold, excellent surface complementarity to the simulated binding pocket, and concordance with experimentally derived SAR data.
authors.affiliation: Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Grienke
authors.forename: Michaela
authors.initials: M
authors.lastname: Schmidtke
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.forename: Kathrin
authors.initials: K
authors.lastname: Pfarr
authors.forename: Peter
authors.initials: P
authors.lastname: Wutzler
authors.forename: Ralf
authors.initials: R
authors.lastname: Dürrwald
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Liedl
authors.forename: Hermann
authors.initials: H
authors.lastname: Stuppner
authors.forename: Judith M
authors.initials: JM
authors.lastname: Rollinger
mesh_terms: D032429:Alpinia / Q000737:chemistry*; D000998:Antiviral Agents / Q000302:isolation & purification / Q000494:pharmacology*; D036381:Diarylheptanoids / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D056004:Molecular Dynamics Simulation; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D008517:Phytotherapy; D010946:Plants, Medicinal / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D036381:Diarylheptanoids; D009439:Neuraminidase