In silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone receptor antagonist properties

摘要

Prostacyclin (PGI(2)) 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) beta/delta. 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 PGI(2), beraprost (IP receptor agonist), and GW0742 (PPAR beta/delta agonist), to bind to nuclear receptors, confirmed with pharmacological methods. In silico screening predicted that PGI(2), beraprost, and GW0742 have the potential to bind to different nuclear receptors, in particular thyroid hormone beta receptor (TR beta) and thyroid hormone alpha receptor (TR alpha). 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 TR beta and TR alpha antagonistic properties; beraprost IC50 6.3 x 10(-5) mol/L and GW0742 IC50 4.9 x 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 TR beta and TR alpha antagonist behaviour, and suggests that PGI(2) has the ability to affect the long term function of cells through binding to and inactivating thyroid hormone receptors. (C) 2015 Elsevier Inc. All rights reserved.