J Chem Inf Model. 2026 Jun 30. doi: 10.1021/acs.jcim.6c00912. Online ahead of print.
ABSTRACT
Synthetic ligands of retinoic acid receptor γ (RARγ) and vitamin D receptor (VDR) can act as agonists or antagonists by reshaping receptor conformation and cofactor recruitment, yet the structural and energetic determinants of this selectivity remain incompletely defined. Here, we present an integrated structural and thermodynamic analysis combining conformational characterization, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations to compare representative agonists and antagonists of human RARγ and VDR. Binding free energies and effective enthalpic contributions were evaluated for selected ligands, whereas the apparent entropic term, estimated indirectly as –TΔSapp = ΔGbind – ΔHeff, was used only as a qualitative internal descriptor. The thermodynamic profiles indicate that effective enthalpic stabilization is a more informative comparative descriptor than binding free energy alone, with clear agonist-antagonist separation for RARγ and a directional, less statistically resolved trend for VDR. These energetic patterns were interpreted alongside ligand-dependent stabilization of helix 12 and receptor-ligand interaction networks. Newly determined MicroED structures of AGN194310 and AGN205728 were incorporated as ligand-specific conformational references, improving structural definition without being treated as direct evidence of receptor-bound bioactive conformations. Comparative analysis of RARγ and VDR suggests that functional selectivity is not governed solely by affinity but emerges from the interplay among ligand-binding energetics, interaction networks, and receptor conformational dynamics. These results provide a retrospective mechanistic benchmark for interpreting agonist- and antagonist-associated behavior in nuclear receptors and may guide future studies on functionally selective modulators.
PMID:42378554 | DOI:10.1021/acs.jcim.6c00912
