Journal: Toxicological Sciences In silico identification and pharmacological evaluation of novel endocrine disrupting chemicals that act via the ligand binding domain estrogen receptor α

Endocrine disrupting chemicals (EDCs) pose a significant threat to human health, society and the environment. Many EDCs elicit their toxicological effects through nuclear hormone receptors, like the estrogen receptor α (ERα). In silico models can be used to prioritize chemicals for toxicological evaluation to reduce the amount of costly pharmacological testing and enable early alerts for newly designed compounds. However, many of the current computational models are overly dependent on the chemistry of known modulators and perform poorly for novel chemical scaffolds. Herein we describe the development of computational, three-dimensional multiconformational-pocket-field docking and chemical-field docking models for the identification of novel EDCs that act via the ligand-binding domain of ERα. These models were highly accurate in the retrospective task of distinguishing known high-affinity ERα modulators from inactive or decoy molecules, with minimal training. To illustrate the utility of the models in prospective in silico compound screening, we screened a database of over 6,000 environmental chemicals and evaluated the 24 top-ranked hits in a ERα transcriptional activation assay and a differential scanning fluorimetry-based ERα binding assay. Promisingly, six chemicals displayed ERα agonist activity (32nM to 3.98μM) and two chemicals had moderately stabilizing effects on ERα. Two newly identified active compounds were chemically related β-adrenergic receptor (βAR) agonists, dobutamine and ractopamine (a feed additive that promotes leanness in cattle and poultry), which are the first βAR agonists identified as activators of ERα-mediated gene transcription. This approach can be applied to other receptors implicated in endocrine disruption.