Dual-site binding of BPA analogs to thyroid receptor alpha: A comprehensive computational study with relevance to autoimmunity and toxicological assessment

Bisphenol A (BPA) is an endocrine disruptor that can bind to thyroid receptor alpha (TRα) and interfere with thyroid hormone signaling, a pathway implicated in thyroid autoimmunity in previous studies. As regulatory pressure drives the use of BPA analogs, concerns remain about whether these substitutes are safer than BPA. This study evaluated the interactions of BPA analogs with the ligand-binding domain (LBD) and allosteric site (AS) of TRα. Molecular docking was performed using AutoDock Vina and jdock, with triiodothyronine (T3) and BPA as reference ligands. Top-ranked complexes were further examined using 200 ns molecular dynamics simulations and MM-PBSA binding free-energy calculations. Density functional theory (DFT) was used to assess electronic properties, while absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling provided additional information on their predicted toxicological characteristics. Several analogs, particularly BisOPP-A and Bisphenol P, showed stronger predicted binding to TRα than BPA at both sites. BisOPP-A showed binding energies of −10.632 and − 10.89 kcal/mol at the LBD with Autodock Vina and jdock, respectively, compared with −8.728 and − 8.85 kcal/mol for BPA. MM-PBSA further supported stronger BisOPP-A binding than BPA at the LBD (−41.96 vs −24.87 kcal/mol), together with measurable conformational changes in TRα. Overall, several analogs retained BPA-like characteristics while showing stronger predicted TRα interactions, indicating that structural substitution does not necessarily reduce thyroid receptor activity. These findings support further experimental validation of BPA analogs and integrated in silico approaches for early chemical risk assessment.