A Computational Framework to Evaluate Interactions of BPA and Its Analogs with Human Liver X Receptor-Beta for Health Risk Assessment

Bisphenols are widely used in industrial applications to produce plastics and other consumer products. Among them, bisphenol A (BPA) is the most extensively studied due to its well-documented endocrine-disrupting effects and its association with various health conditions, including metabolic disorders and liver disease. Due to its known toxicity, BPA use has been restricted in many countries, leading to the emergence of several structural analogs. Recent studies have shown that BPA can interfere with normal liver metabolism by interacting with Liver X Receptor-beta (LXRβ). Although some BPA analogs have also been reported to cause toxicity, their exact effects on LXRβ remain unclear. In this study, we investigated the interaction between BPA analogs and LXRβ using molecular docking. BPA and the known LXRβ ligand G58 were used as reference compounds. The top 10 BPA analogs were further evaluated for their pharmacokinetics and pharmacodynamics properties. Molecular dynamics simulations over 100 ns were performed to study the dynamic behavior of LXRβ in complex with these analogs. Binding free energies were then calculated using the MM-PBSA method. Our results showed that several BPA analogs exhibited predicted stronger binding activities to LXRβ than BPA. Although some analogs shared similar pharmacokinetic and pharmacodynamic profiles with BPA, their stronger interaction with LXRβ raises concerns about their potential hepatotoxicity. This study employs a robust <i>in silico</i> framework to predict that commonly used BPA alternatives may pose a greater potential hepatotoxic risk than the banned parent compound, highlighting the value of computational approaches in prioritizing chemicals for further experimental assessment.