Thyroid Hormone Receptor Antagonists: From Environmental Pollution to Novel Small Molecules

Conformational Changes of Thyroid Receptors in Response to Antagonists

“…As shown in Table , there is a distinct ligand specificity of the TR isoforms regarding the interactions with the selected antagonists. Various experimental techniques have been applied to study the isotype-specific effects of the selected compounds as shown in a recent review . As studies for some compounds were conducted on either TRα or TRβ, we cannot exclude their binding to the other isoform.…”

“…Thyroid hormone receptors (TRs) belong to the superfamily of nuclear receptors (NRs) and are involved in a multitude of physiological and pathological processes in humans. In particular, they mediate the action of thyroid hormones, which play a critical role in development, growth, cardiac function, and metabolism leading to severe implications in the case of dysregulation. , The isoforms TRα and TRβ present different tissue distributions as well as a distinct physiological role beyond their expression patterns. This was, for example, shown by the isoform-specific regulation of gene expression .…”

“…Even though therapeutics against hyperthyroidism is available, they suffer from considerable disadvantages such as the highly delayed onset of synthesis inhibitors due to a remaining reserve of hormones in circulation and their long half-life. Thus, direct pharmacological intervention at the receptor level instead of thyroid hormone synthesis has appealing benefits. ,,− Interestingly, the cardiovascular adverse effects of the analgesic celecoxib were linked to TRβ antagonism . In contrast, it was proposed that TRs might constitute a target for novel antiarrhythmics due to their influence on the cardiovascular system.…”

“…However, despite their therapeutic potential in rapidly treating thyrotoxicosis, TR antagonists have not yet reached clinical application. , In this regard, the understanding of the underlying structural mechanism of TR antagonism can be critical for the development of effective compounds, especially in a structure-based design setting as it was evidenced in previous discovery efforts . Since crystal structures of TRα or TRβ bound to antagonists have not been published and experimental methods fail to provide atomistic detail, computational methods offer an attractive approach to acquire mechanistic insight into their structural adaptations in response to antagonists. ,,,− In previous work, the unliganded ligand binding domain (LBD) of TRβ was examined with 22 ns molecular dynamics (MD) simulations and the mechanism of TR antagonism was monitored by hydrogen/deuterium exchange followed by mass spectrometry. Based on these experiments, it was illustrated that helix-12 (H12) underwent conformational changes .…”

Beta-Blockers for Shelter From the Storm*

“…There are leads for inhibiting the carrier (9). Furthermore, amiodarone has nonspecific receptor blocking ability, and better prospects are under investigation (10, 11). However, it is worrisome that amiodarone is a drug that may precipitate a storm.…”