title: GRID and docking analyses reveal a molecular basis for flavonoid inhibition of Src family kinase activity.
abstract: Flavonoids reduce cardiovascular disease risk through anti-inflammatory, anti-coagulant and anti-platelet actions. One key flavonoid inhibitory mechanism is blocking kinase activity that drives these processes. Flavonoids attenuate activities of kinases including phosphoinositide-3-kinase, Fyn, Lyn, Src, Syk, PKC, PIM1/2, ERK, JNK and PKA. X-ray crystallographic analyses of kinase-flavonoid complexes show that flavonoid ring systems and their hydroxyl substitutions are important structural features for their binding to kinases. A clearer understanding of structural interactions of flavonoids with kinases is necessary to allow construction of more potent and selective counterparts. We examined flavonoid (quercetin, apigenin and catechin) interactions with Src family kinases (Lyn, Fyn and Hck) applying the Sybyl docking algorithm and GRID. A homology model (Lyn) was used in our analyses to demonstrate that high-quality predicted kinase structures are suitable for flavonoid computational studies. Our docking results revealed potential hydrogen bond contacts between flavonoid hydroxyls and kinase catalytic site residues. Identification of plausible contacts indicated that quercetin formed the most energetically stable interactions, apigenin lacked hydroxyl groups necessary for important contacts and the non-planar structure of catechin could not support predicted hydrogen bonding patterns. GRID analysis using a hydroxyl functional group supported docking results. Based on these findings, we predicted that quercetin would inhibit activities of Src family kinases with greater potency than apigenin and catechin. We validated this prediction using in vitro kinase assays. We conclude that our study can be used as a basis to construct virtual flavonoid interaction libraries to guide drug discovery using these compounds as molecular templates.
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, RG6 6UB Berkshire, UK. Electronic address: b.wright@reading.ac.uk.
authors.forename: Bernice
authors.initials: B
authors.lastname: Wright
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, RG6 6UB Berkshire, UK.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Watson
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, RG6 6UB Berkshire, UK.
authors.forename: Liam J
authors.initials: LJ
authors.lastname: McGuffin
authors.affiliation: Hugh Sinclair Unit of Human Nutrition, University of Reading, Reading, RG6 6UB Berkshire, UK.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lovegrove
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, RG6 6UB Berkshire, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gibbins
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D047310:Apigenin / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002392:Catechin / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051572:Proto-Oncogene Proteins c-hck / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D047310:Apigenin; D000255:Adenosine Triphosphate; D002392:Catechin; D011794:Quercetin; C496631:HCK protein, human; D051572:Proto-Oncogene Proteins c-hck; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases
keywords: Anti-platelet agents and flavonoids; Cardiovascular disease and flavonoids; Flavonoid computational studies; Flavonoid molecular templates; GRID; Selective flavonoid-based analogues; Sybyl docking