Design of thyroid hormone receptor antagonists from first principles

Paul Webb, Ngoc Ha Nguyen, Grazia Chiellini, Hikari A.I. Yoshihara, Suzana T. Cunha Lima, James W. Apriletti, Ralff C.J. Ribeiro, Adhirai Marimuthu, Brian L. West, Patrick Goede, Karin Mellstrom, Stefan Nilsson, Peter J. Kushner, Robert J. Fletterick, Thomas S. Scanlan, John D. Baxter

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)59-73
Number of pages15
JournalJournal of Steroid Biochemistry and Molecular Biology
Issue number1-5
StatePublished - Dec 2002


  • Thyroid hormone antagonists
  • Thyroid hormone receptor

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology


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