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dc.contributor.authorPerez Diaz, Noelia
dc.contributor.authorZloh, Mire
dc.contributor.authorPatel, Pryank
dc.contributor.authorMacKenzie, Louise Susan
dc.identifier.citationPerez Diaz , N , Zloh , M , Patel , P & MacKenzie , L S 2016 , ' In silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone beta receptor antagonist properties. ' , Prostaglandins and Other Lipid Mediators , vol. 122 , pp. 18-27 .
dc.identifier.otherPURE: 8617203
dc.identifier.otherPURE UUID: 6465f364-30fb-40b1-aa89-bb1e00d31631
dc.identifier.otherScopus: 84952670452
dc.description.abstractProstacyclin (PGI2) is a key mediator involved in cardiovascular homeostasis, acting predominantly on two receptor types; cell surface IP receptor and cytosolic peroxisome proliferator activated receptor (PPAR) β/δ. Having a very short half-life, direct methods to determine its long term effects on cells is difficult, and little is known of its interactions with nuclear receptors. Here we used computational chemistry methods to investigate the potential for PGI2, beraprost (IP receptor agonist), and GW0742 (PPARβ/δ agonist), to bind to nuclear receptors, confirmed with pharmacological methods. In silico screening predicted that PGI2, beraprost, and GW0742 have the potential to bind to different nuclear receptors, in particular thyroid hormone β receptor (TRβ) and thyroid hormone α receptor (TRα). Docking analysis predicts a binding profile to residues thought to have allosteric control on the TR ligand binding site. Luciferase reporter assays confirmed that beraprost and GW0742 display TRβ and TRα antagonistic properties; beraprost IC50 6.3 × 10−5 mol/L and GW0742 IC50 4.9 × 10−6 mol/L. Changes to triiodothyronine (T3) induced vasodilation of rat mesenteric arteries measured on the wire myograph were measured in the presence of the TR antagonist MLS000389544 (10−5 mol/L), beraprost (10−5 mol/L) and GW0742 (10−5 mol/L); all significantly inhibited T3 induced vasodilation compared to controls. We have shown that both beraprost and GW0742 exhibit TRβ and TRα antagonist behaviour, and suggests that PGI2 has the ability to affect the long term function of cells through binding to and inactivating thyroid hormone receptors.en
dc.relation.ispartofProstaglandins and Other Lipid Mediators
dc.titleIn silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone beta receptor antagonist properties.en
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionMedicinal and Analytical Chemistry
dc.contributor.institutionCentre for Hazard Detection and Protection Research
dc.contributor.institutionDepartment of Pharmacy, Pharmacology and Postgraduate Medicine
dc.contributor.institutionBiochemistry and Bioinformatics
dc.contributor.institutionDepartment of Biological and Environmental Sciences
dc.contributor.institutionDepartment of Human and Environmental Sciences
dc.contributor.institutionHealth & Human Sciences Research Institute
dc.contributor.institutionPharmacology and Clinical Science Research
dc.contributor.institutionAgriculture, Veterinary and Food Sciences
dc.contributor.institutionCardiovascular Pathologies
dc.contributor.institutionDiabetic neuropathies
dc.contributor.institutionBiosciences Research Group
dc.description.statusPeer reviewed
dc.relation.schoolSchool of Life and Medical Sciences
rioxxterms.typeJournal Article/Review

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