Structure-based design of novel THR-β agonists and mechanism of activation research by molecular dynamics simulations

Thyroid hormone receptor β (THR-β) plays a crucial role in regulating lipid metabolism, steatohepatitis, and liver fibrosis. The approval of Resmetirom has demonstrated the therapeutic potential of THR-β agonism in treating metabolic-associated steatohepatitis (MASH). Therefore, investigating the mechanism of THR-β activation is essential for understanding its mode of action and further research. In this study, we report a newly designed THR-β agonist, D4, which exhibits superior in vitro activity, with a Ki value of 257.3 nM, providing a valuable tool for exploring receptor activation. To gain mechanistic insights, we conducted 500 ns molecular dynamics (MD) simulations on three systems: THR-β bound to agonist D4, THR-β bound to a known antagonist 6, and apo THR-β (ligand-free). A detailed analysis of the structural stability and activation mechanism of these systems was performed. Our findings suggest a novel activation mechanism in which a dynamic salt bridge relay, mediated by Loop-H11-H12, stabilizes the active state of the receptor. In addition, key hydrophobic interaction formed by antagonist and carbon chain of Arg438 was found to be crucial for ligands to switch from agonist to antagonist.