title: In silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone receptor antagonist properties.
abstract: Prostacyclin (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.
authors.affiliation: Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK.
authors.forename: Noelia
authors.initials: N
authors.lastname: Perez Diaz
authors.affiliation: Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK.
authors.forename: Mire
authors.initials: M
authors.lastname: Zloh
authors.affiliation: Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK.
authors.forename: Pryank
authors.initials: P
authors.lastname: Patel
authors.affiliation: Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK. Electronic address: l.mackenzie2@herts.ac.uk.
authors.forename: Louise S
authors.initials: LS
authors.lastname: Mackenzie
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D009213:Myography / Q000379:methods; D000072417:Protein Domains; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D037021:Thyroid Hormone Receptors alpha / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D011464:Epoprostenol; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D013844:Thiazoles; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; C048081:beraprost; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds
keywords: Beraprost; MLS; MLS000389544; Mesenteric artery; NSAID; PAH; PGI(2); PPAR; PPARβ/δ; Prostacyclin; T3; TRα; TRβ; Thyroid hormone; Triiodothyronine; non-steroidal anti-inflammatory drug; peroxisome proliferator activated receptor; prostacyclin; pulmonary artery hypertension; thyroid hormone α receptor; thyroid hormone β receptor; triiodothyronine