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.

Computational Molecular Docking and X-ray Crystallographic Studies of Catechins in New Drug Design Strategies

“…The findings by Wright et al predict that quercetin would inhibit the activity of Src family kinases with greater potency than apigenin and catechin. This prediction was confirmed using in vitro kinase assays [ 80 ].…”

“…A clearer understanding of structural interactions between flavonoids and kinases is necessary to allow the construction of more potent and selective counterparts. Wright et al examined the interactions of quercetin, apigenin and catechin with Src family kinases (Lyn, Fyn and Hck) by several methods, including CMDA, and revealed potential hydrogen bond contacts between flavonoid hydroxyls and kinase catalytic site residues [ 80 ]. Quercetin formed the most energetically stable interactions, apigenin lacked the hydroxyl groups necessary for important contacts and the non-planar structure of catechin could not support predicted hydrogen bonding patterns.…”

Role of flavonoids and nitrates in cardiovascular health

“…al have shown quercetin-3glucuronide to potently inhibit protein disulphide isomerase (PDI), an oxidoreductase important in thrombus formation (80) . X-ray crystallographic analyses of flavonoid-kinase complexes have shown that flavonoid ring systems and the hydroxyl groups are important features for kinase binding (81) (82) supporting the evidence for structure-specific effects on platelet function. Taken…”

Physiologically based kinetic modeling of hesperidin metabolism and its use to predict in vivo effective doses in humans

“…A protein kinase A (PKA) inhibition assay was carried to measure the potency of hesperetin and its monoglucuronides H‐7G and H‐3′G to inhibit PKA as possible mechanism underlying some of its beneficial effects . The PKA inhibition assay was carried out based on the method described by Chen et al.…”