Premium
Molecular structure‐function relationship of dietary polyphenols for inhibiting VEGF‐induced VEGFR‐2 activity
Author(s) -
Cerezo Ana B.,
Winterbone Mark S.,
Moyle Christina W. A.,
Needs Paul W.,
Kroon Paul A.
Publication year - 2015
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201500407
Subject(s) - polyphenol , chemistry , potency , ellagic acid , ic50 , biochemistry , in silico , pharmacology , in vitro , stereochemistry , antioxidant , biology , gene
Scope 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. Methods and results The concentration of polyphenol required to cause 50% inhibition (IC 50 ) 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 IC 50 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. Conclusion 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.