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dc.contributor.authorWright, Bernice
dc.contributor.authorWatson, Kimberly A
dc.contributor.authorMcGuffin, Liam J
dc.contributor.authorLovegrove, Julie A
dc.contributor.authorGibbins, Jonathan M
dc.date.accessioned2019-08-14T11:30:11Z
dc.date.available2019-08-14T11:30:11Z
dc.date.issued2015-06-09
dc.identifier.citationWright, B., Watson, K. A., McGuffin, L. J., Lovegrove, J. A. and Gibbins, J. M. (2015) GRID and docking analyses reveal a molecular basis for flavonoid inhibition of Src family kinase activity, The Journal of Nutritional Biochemistry, 26(11), pp. 1156-1165.en
dc.identifier.issn0955-2863en
dc.identifier.doi10.1016/j.jnutbio.2015.05.004en
dc.identifier.urihttp://hdl.handle.net/2436/622646
dc.description.abstractFlavonoids 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.en
dc.formatapplication/PDFen
dc.languageen
dc.language.isoenen
dc.publisherElsevier BVen
dc.relation.urlhttps://www.sciencedirect.com/science/article/pii/S0955286315001370?via%3Dihuben
dc.subjectFlavonoid molecular templatesen
dc.subjectGRIDen
dc.subjectSybyl dockingen
dc.subjectSelective flavonoid-based analoguesen
dc.subjectFlavonoid computational studiesen
dc.subjectCardiovascular disease and flavonoidsen
dc.subjectAnti-platelet agents and flavonoidsen
dc.titleGRID and docking analyses reveal a molecular basis for flavonoid inhibition of Src family kinase activityen
dc.typeJournal articleen
dc.identifier.journalThe Journal of Nutritional Biochemistryen
dc.date.updated2019-08-12T13:20:10Z
dc.date.accepted2015-05-08
rioxxterms.funderUniversity of Wolverhamptonen
rioxxterms.identifier.projectUOW140819BWen
rioxxterms.versionAMen
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
rioxxterms.licenseref.startdate2019-08-14en
dc.source.volume26
dc.source.issue11
dc.source.beginpage1156
dc.source.endpage1165
dc.description.versionPublished version
refterms.dateFCD2019-08-14T11:29:09Z
refterms.versionFCDAM
refterms.dateFOA2019-08-14T11:30:12Z


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