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Mol Nutr Food Res. 2015 Nov;59(11):2119-31. doi: 10.1002/mnfr.201500407. Epub 2015 Sep 8.

Molecular structure-function relationship of dietary polyphenols for inhibiting VEGF-induced VEGFR-2 activity.

Author information

1
Food & Health Programme, Institute of Food Research, Norwich Research Park, Norwich, UK.
2
Nutrición y Bromatología, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.

Abstract

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 (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.

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.

KEYWORDS:

Angiogenesis; Atherosclerosis; Binding affinity; Flavonoids; Phenolics

PMID:
26250940
PMCID:
PMC4973850
DOI:
10.1002/mnfr.201500407
[Indexed for MEDLINE]
Free PMC Article

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