title: Structure-activity relationships of fraxamoside as an unusual xanthine oxidase inhibitor.
abstract: Fraxamoside, a macrocyclic secoiridoid glucoside featuring a hydroxytyrosol group, was recently identified as a xanthine oxidase inhibitor (XOI) comparable in potency in vitro to the standard antigout drug allopurinol. However, this activity and its considerably higher value than its derivatives oleuropein, oleoside 11-methyl ester, and hydroxytyrosol are not explained by structure-activity relationships (SARs) of known XOIs. To exclude allosteric mechanisms, we first determined the inhibition kinetic of fraxamoside. The resulting competitive mechanism prompted a computational SAR characterization, combining molecular docking and dynamics, which fully explained the behavior of fraxamoside and its derivatives, attributed the higher activity of the former to conformational properties of its macrocycle, and showed a substantial contribution of the glycosidic moiety to binding, in striking contrast with glycoside derivatives of most other XOIs. Overall, fraxamoside emerged as a lead compound for a new class of XOIs potentially characterized by reduced interference with purine metabolism.
authors.affiliation: a Institute of Biomolecular Chemistry (ICB) , National Council Research (CNR) of Italy , Pozzuoli , Italy.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Vitale
authors.affiliation: b Department of Medicine and Health Sciences , University of Molise , Campobasso , Italy.
authors.forename: Lina
authors.initials: L
authors.lastname: Antenucci
authors.affiliation: a Institute of Biomolecular Chemistry (ICB) , National Council Research (CNR) of Italy , Pozzuoli , Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Gavagnin
authors.affiliation: b Department of Medicine and Health Sciences , University of Molise , Campobasso , Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Raimo
authors.affiliation: a Institute of Biomolecular Chemistry (ICB) , National Council Research (CNR) of Italy , Pozzuoli , Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Amodeo
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D039823:Iridoids / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D013329:Structure-Activity Relationship; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D039823:Iridoids; C000614524:fraxamoside; D014969:Xanthine Oxidase
keywords: Fraxamoside; molecular modelling; natural product; xanthine oxidase inhibitor