Halogen bonding as a potential mechanism for inhibition of thyroid hormone activation

Deiodination by iodothyronine deiodinases (Dios) is essential to maintain thyroid hormone (TH) homeostasis. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are known endocrine disruptors. PBDEs and their hydroxylated metabolites (OH-BDEs) have been shown to inhibit Dio, while evidence for PCB inhibition are limited. These xenobiotics could inhibit Dio activity by competitively binding to the active site Sec through halogen bonding (XB) to prevent deiodination. XB interactions calculated using density functional theory (DFT) arrange XB strengths in the order THs > PBDEs > PCBs in agreement with known XB trends. These trends are consistent with the ordering of the lowest energy C–X*-type unoccupied orbitals (I < Br < Cl) which overlap with the Se lp donor. The higher energy C–Br* and C–Cl* orbitals give weaker donor-acceptor complexes and less activation of the C–X bond. Comparison of the XB interaction energies suggests that a threshold XB strength may be required for dehalogenation. Only highly brominated PBDEs have binding energies in the same range as THs, suggesting that these compounds could undergo debromination.