title: Molecular structure-function relationship of dietary polyphenols for inhibiting VEGF-induced VEGFR-2 activity.
abstract: METHODS
  We recently reported potent inhibition of VEGF signalling by two flavanols at sub-micromolar concentrations, mediated by direct binding of the flavanols to VEGF. The aim of this study was to quantify the inhibitory potency and binding affinity of a wide range of dietary polyphenols and determine the structural requirements for VEGF inhibition.
  
  
  RESULTS
  The concentration of polyphenol required to cause 50% inhibition (IC50 ) of VEGF-dependent VEGFR-2 activation in HUVECS was determined after pretreating VEGF with polyphenols at various concentations. Binding affinities and binding sites on VEGF were predicted using in-silico modelling. Ellagic acid and 15 flavonoids had IC50 values ≤10 μM while 28 other polyhenols were weak/non-inhibitors. Structural features associated with potent inhibition included 3-galloylation, C-ring C2=C3, total OH, B-ring catechol, C-ring 3-OH of flavonoids. Potency was not associated with polyphenol hydrophobicity. There was a strong correlation between potency of inhibition and binding affinities, and all polyphenols were predicted to bind to a region on VEGF involved in VEGFR-2 binding.
  
  
  CONCLUSIONS
  Specific polyphenols bind directly to a discrete region of VEGF and inhibit VEGF signalling, and this potentially explains the associations between consumption of these polyphenols and CVD risk.
authors.affiliation: Food & Health Programme, Institute of Food Research, Norwich Research Park, Norwich, UK.|Nutrición y Bromatología, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Cerezo
authors.affiliation: Food & Health Programme, Institute of Food Research, Norwich Research Park, Norwich, UK.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Winterbone
authors.affiliation: Food & Health Programme, Institute of Food Research, Norwich Research Park, Norwich, UK.
authors.forename: Christina W A
authors.initials: CW
authors.lastname: Moyle
authors.affiliation: Food & Health Programme, Institute of Food Research, Norwich Research Park, Norwich, UK.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Needs
authors.affiliation: Food & Health Programme, Institute of Food Research, Norwich Research Park, Norwich, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Kroon
mesh_terms: D002478:Cells, Cultured; D004032:Diet; D005419:Flavonoids / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D006900:Hydroxylation; D008745:Methylation; D059808:Polyphenols / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D005419:Flavonoids; D059808:Polyphenols; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Atherosclerosis; Binding affinity; Flavonoids; Phenolics