Halogen Bonding in the Molecular Recognition of Thyroid Hormones and Their Metabolites by Transport Proteins and Thyroid Hormone Receptors

Abstract

Halogen bonding (XB) is an attractive interaction between a
halogen atom and an electron donor. Although halogens are electronrich
atoms, they act as electrophiles in these types of interactions. This is
due to the presence of a significant positive charge (σ-hole) on the halogen
atoms in organic halides along the R-X (R = carbon, nitrogen, halogen)
bond. With an increase in the polarizability down the group from
fluorine to iodine, the positive charge on the σ-hole increases, which
leads to an increase in the strength of XB. Numerous studies revealed
that XB is a useful tool to develop supramolecular architectures by selfassembly.
Interestingly, XBs are also observed in many biomolecules,
such as protein–ligand complexes and nucleic acids containing halogenated
nucleotides. In fact, XBs are extensively used to increase the
potency and selectivity of small molecule ligands to a target protein. In
this minireview, we discuss the role of XBs in the molecular recognition
of thyroid hormones (THs) and their metabolites by various transport
proteins and thyroid hormone receptors (TRs). THs are naturally occurring
iodinated small molecules that are synthesized by the thyroid gland
and carried to various target organs by several serum transport proteins,
such as transthyretin, human serum albumin, and thyroxine-binding
globulin. Interestingly, all these proteins form XBs with THs and these
interactions play important roles in the high affinity binding. Furthermore,
TRs, such as TRα and TRβ also form XBs with the 3-iodine of THs and
triiodothyroacetic acid, an endogenous TH metabolite that shows thyromimetic
activity.