Design of thyroid hormone receptor antagonists from first principles

Area of Science:

• Endocrinology and Metabolism
• Molecular Pharmacology
• Structural Biology

Background:

• Thyroid hormone receptor (TR) antagonists are sought for treating hyperthyroidism and related conditions.
• TR agonists bind within the ligand-binding domain (LBD), necessitating specific structural interactions for activity.
• Understanding TR LBD structure is crucial for rational drug design.

Purpose of the Study:

• To design novel TR antagonists based on TR crystal structure information.
• To investigate the impact of ligand extensions on TR LBD conformation and activity.
• To identify potent TR antagonists for potential therapeutic applications.

Main Methods:

• Structure-based drug design of TR ligands with extensions at the 5' aryl position.
• Synthesis of novel compounds, including DIBRT, NH-3, GC-14, and NH-4.
• In vitro assays to determine antagonist/agonist activity and binding affinities.
• In vivo studies using an animal model to assess TR antagonist efficacy.

Main Results:

• Several synthetic ligands with 5' aryl ring extensions demonstrated antagonist or partial antagonist activity.
• Compound NH-3 emerged as a potent TR antagonist with nanomolar affinity.
• NH-3 effectively inhibited TR action in an animal model, representing a significant therapeutic advance.
• Unexpectedly, NH-3 blocked both co-activator and co-repressor binding, challenging typical antagonist mechanisms.
• Some extended ligands unexpectedly functioned as full or partial agonists.

Conclusions:

• Ligand extensions, particularly at the 5' aryl position, can effectively yield TR antagonists by disrupting helix 12 positioning.
• NH-3 represents a novel, potent TR antagonist with demonstrated in vivo efficacy.
• The complex binding and activity profiles of these ligands suggest dynamic conformational equilibria within the TR LBD.