Recent advances in the molecular modeling of estrogen receptor-mediated toxicity

In the past two decades, there has been increasing concern about the potentially adverse effects of exogenous endocrine active substances (EAS) that alter the function of the endocrine system by interfering with hormone regulation. The mechanistic pathways by which EAS may elicit adverse effects, such as developmental and reproductive toxicity, often involve direct binding to nuclear hormone receptors. Certainly, the best studied nuclear receptor is the estrogen receptor (ER). Large-scale in vitro and in vivo methods have been developed to assess the estrogenic toxicity of chemicals. However, there are financial and animal welfare concerns related to their application. Quantitative structure-activity relationship (QSAR) approaches have proven their utility as a priority setting tool in the risk assessment of EAS. In addition, the models help to clarify the binding mode of the interacting substances. As estrogen-mediated effects are usually related to ligand-receptor interactions, and as there have been comprehensive structural studies on the ER, molecular modeling together with other in silico approaches provide a suitable means of studying these estrogenic effects. This chapter provides an overview of the molecular modeling approaches applied to ligand-ER interactions. The progress in the field is outlined, and some critical issues are analyzed based on recently published models where these approaches are applied.