Structural analysis of selective agonists of thyroid hormone receptor β using 3D-QSAR and molecular docking

Selective thyroid hormone receptor β (TRβ) binding over TRα is an important requirement for improved therapeutic profile of TRβ agonists. Since selective compounds might be tolerated at doses that lead to complete binding without side effects, thus a selectivity study is valuable. Initially, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were developed on a series of agonists of TRβ and TRα, respectively. These models produced statistically significant results: TRβ-CoMFA (Rcv2, Rpred2: 0.634, 0.6825), TRβ-CoMSIA (Rcv2, Rpred2: 0.711, 0.5622), TRα-CoMFA (Rcv2, Rpred2: 0.602, 0.5384) and TRα-CoMSIA (Rcv2, Rpred2: 0.674, 0.5078). These cross-validated results suggest that the developed models have excellent internal and external predictability and consistency. To further explore the origin of the selectivity at the amino acid residue level, the comparison between molecular docking and contour maps was conducted, it is revealed that steric, electrostatic and hydrogen bonding interactions play critical roles on selectivity; and Arg316, Arg282, Asn331, His435 for TRβ, Arg228, Arg262, Ser277, His381 for TRα are the significant residues, an in-depth comparative investigation suggests that the single different amino acid Asn331/Ser277 in the ligand binding pocket mainly introduce the ligand selectivity. All these analyses provide valuable information for better understand the mechanism of ligand-receptor interaction and facilitate structural modifications of the agonists to increase activity and selectivity.