title: Inhibitory potency of flavonoid derivatives on influenza virus neuraminidase.
abstract: The constant risk of emerging new influenza virus strains that are resistant to established inhibitors like oseltamivir leaves influenza neuraminidase (NA) a prominent target for drug design. The inhibitory activity of several flavonoid derivatives was experimentally tested in comparison to oseltamivir for the NA expressed by the seasonal influenza virus strains A/California/7/09 (A(H1N1)pdm09), A/Perth/16/09 (A(H3N2)), and B/Brisbane/60/08. IC50 values of polyphenols confirmed moderate inhibition in the μM range. Structurally, the amount and site of glycosylation of tested flavonoids have no significant influence on their inhibitory potency. In a pharmacophore-based docking approach the structure-activity relationship was evaluated. Molecular dynamics simulations revealed highly flexible parts of the enzyme and the contribution of salt bridges to the structural stability of NA. The findings of this study elucidate the impact of flavonoids on viral neuraminidase activity and the analysis of their modes of action provide valuable information about the mechanism of NA inhibition.
authors.affiliation: Freie Universitaet Berlin, Institute of Pharmacy, Koenigin-Luise Str. 2/4, 14195 Berlin, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Rakers
authors.affiliation: Division of Influenza and other Respiratory Viruses, Robert Koch-Institut, Seestr. 10, 13353 Berlin, Germany.
authors.forename: Sverre-Morten
authors.initials: SM
authors.lastname: Schwerdtfeger
authors.affiliation: Freie Universitaet Berlin, Institute of Pharmacy, Koenigin-Luise Str. 2/4, 14195 Berlin, Germany.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Mortier
authors.affiliation: Division of Influenza and other Respiratory Viruses, Robert Koch-Institut, Seestr. 10, 13353 Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Duwe
authors.affiliation: Division of Influenza and other Respiratory Viruses, Robert Koch-Institut, Seestr. 10, 13353 Berlin, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wolff
authors.affiliation: Freie Universitaet Berlin, Institute of Pharmacy, Koenigin-Luise Str. 2/4, 14195 Berlin, Germany. Electronic address: gerhard.wolber@fu-berlin.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.affiliation: Freie Universitaet Berlin, Institute of Pharmacy, Koenigin-Luise Str. 2/4, 14195 Berlin, Germany. Electronic address: melzig@zedat.fu-berlin.de.
authors.forename: Matthias F
authors.initials: MF
authors.lastname: Melzig
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D009980:Influenza A virus / Q000201:enzymology*; D009981:Influenza B virus / Q000201:enzymology*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D009439:Neuraminidase
keywords: Docking; Flavonoids; Influenza; Molecular dynamics; Neuraminidase