title: Design of thyroid hormone receptor antagonists from first principles.
abstract: It is desirable to obtain TR antagonists for treatment of hyperthyroidism and other conditions. We have designed TR antagonists from first principles based on TR crystal structures. Since agonist ligands are buried in the fold of the TR ligand binding domain (LBD), we reasoned that ligands that resemble agonists with large extensions should bind the LBD, but would prevent its folding into an active conformation. In particular, we predicted that extensions at the 5' aryl position of ligand should reposition helix (H) 12, which forms part of the co-activator binding surface, and thereby inhibit TR activity. We have found that some synthetic ligands with 5' aryl ring extensions behave as antagonists (DIBRT, NH-3), or partial antagonists (GC-14, NH-4). Moreover, one compound (NH-3) represents the first potent TR antagonist with nanomolar affinity that also inhibits TR action in an animal model. However, the properties of the ligands also reveal unexpected aspects of TR behavior. While nuclear receptor antagonists generally promote binding of co-repressors, NH-3 blocks co-activator binding and also prevents co-repressor binding. More surprisingly, many compounds with extensions behave as full or partial agonists. We present hypotheses to explain both behaviors in terms of dynamic equilibrium of H12 position.
authors.affiliation: Diabetes Center and Metabolic Research Unit, University of California, San Francisco, CA 94143, USA. pwebb@itsa.ucsf.edu
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Ngoc-Ha
authors.initials: NH
authors.lastname: Nguyen
authors.forename: Grazia
authors.initials: G
authors.lastname: Chiellini
authors.forename: Hikari A I
authors.initials: HA
authors.lastname: Yoshihara
authors.forename: Suzana T
authors.initials: ST
authors.lastname: Cunha Lima
authors.forename: James W
authors.initials: JW
authors.lastname: Apriletti
authors.forename: Ralff C J
authors.initials: RC
authors.lastname: Ribeiro
authors.forename: Adhirai
authors.initials: A
authors.lastname: Marimuthu
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.forename: Patrick
authors.initials: P
authors.lastname: Goede
authors.forename: Karin
authors.initials: K
authors.lastname: Mellstrom
authors.forename: Stefan
authors.initials: S
authors.lastname: Nilsson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kushner
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fletterick
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
mesh_terms: D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D019281:Dimerization; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D008024:Ligands; D020033:Protein Isoforms; D011988:Receptors, Thyroid Hormone