Assessment of the binding patterns for endo-crine disrupting chemicals in complex with es-trogen and androgen receptors by leveraging the Asclepios Enalos KNIME nodes

Abstract Endocrine Disrupting Chemicals (EDCs) have been shown to mediate metabolic disruptions in human cells and have been associated with severe adverse health effects. By antagonizing the hormones that act on nuclear hormone receptors, like the Estrogen Receptor α (ERα) and the Androgen Receptor (AR), these chemicals disrupt the regulation of various biochemical processes thereby adversely affecting metabolic homeostasis. The expression of estrogen and androgen receptors in the liver and pancreas, which have an important role in lipid and glucose homeostasis regulation, has made them prime targets affected by EDCs. The different chemical structures of EDCs impose limitations on elucidating their binding mechanisms in nuclear receptors. In this context, in silico tools are able to highlight the potential interactions between the chemicals and the receptors. The aim of this study is to apply molecular simulation and experimental techniques to identify common patterns in the binding process of selected EDCs to ERα and AR and thus pinpoint key elements that could be characterized as molecular initiating events (MIE). MM-GBSA, and alchemical relative binding free energy (RBFE) calculations have verified the trends observed in the experimental assays regarding the binding affinity of bisphenol compounds. The findings that confirm the agreement between computational and experimental methods, offer a framework for future studies on the behaviour of ECDs with other metabolically relevant receptors.摘要 内分泌干扰物（Endocrine Disrupting Chemicals，EDCs）已被证实可介导人类细胞的代谢紊乱，且与多种严重的健康不良效应相关联。这类化学物质可通过拮抗结合核激素受体（如雌激素受体α（Estrogen Receptor α，ERα）与雄激素受体（Androgen Receptor，AR））的激素，干扰多种生化过程的调控，进而对代谢稳态产生不利影响。 雌激素受体与雄激素受体在肝脏和胰腺中均有表达，而这两类器官在脂质与葡萄糖稳态调控中发挥关键作用，因此它们成为EDCs的主要作用靶点。EDCs多样的化学结构为阐明其与核受体的结合机制带来了诸多限制。在此背景下，计算机仿真（in silico）工具可有效揭示这类化学物质与受体间的潜在相互作用。 本研究旨在运用分子模拟与实验技术，识别选定EDCs与ERα、AR的结合过程中的共同模式，进而明确可被定义为分子起始事件（Molecular Initiating Events，MIE）的关键要素。MM-GBSA与化学变换相对结合自由能（alchemical relative binding free energy，RBFE）计算，验证了双酚类化合物结合亲和力的实验测定结果趋势。 本研究证实了计算方法与实验方法间的一致性，为后续探究EDCs与其他代谢相关受体的作用行为提供了研究框架。