Molecular docking for screening chemicals of environmental health concern: insight from a case study on bisphenols

To explore the use of molecular docking as a high throughput in silico screening tool for identifying chemicals of environmental health concern, we conducted a case study to assess endocrine disruption effects due to targeting of nuclear receptors (NRs) by chemicals with backbone structures like bisphenols, but with varied functional groups. The molecular docking analysis elucidates how functional groups of the chemicals, such as NH₂, Cl, and OCH₃, influence their interaction with the human estrogen receptor alpha (hERα), a key player in endocrine regulation. Through comparative docking analysis, we examined how bisphenol analogs interact with three distinct conformations of hERα: the apo structure and two structures with bound agonist and antagonist ligands. Water molecules within the protein and surrounding the ligand binding domain (LBD) were found to have little impact on the affinity of compounds binding to the receptor across various conformations. This can be attributed to the hydrophobic nature of the ligand-binding pocket, which consists mainly of hydrophobic amino acid residues and binding sites. In the assessment of bisphenol analogs compared to well established endocrine disrupting chemicals (EDCs), it was observed that these analogs exhibit characteristics commonly associated with endocrine disruptors. While compounds like BPA and BPF exhibited partial agonist activity, stimulating hERα activity to varying degrees, other compounds displayed non-agonist behavior, suggesting a different mode of interaction with the receptor. Further analysis revealed the significance of specific functional groups, such as hydroxyl or amine groups, on the aromatic ring of these compounds in modulating their binding affinity to hERα. Within the ligand binding site of hERα, amino acid residues Glu353, Arg394, and His524 have the capacity to form hydrogen bonds with hydroxyl or amine groups. Protonation or deprotonation of these groups can further alter their binding affinity, thereby influencing their interaction with estrogen receptors and subsequent estrogenic effects. Via this case study, we demonstrate the potential and provide best practices of using molecular docking as a new approach methodology (NAM) for chemical assessments and regulations.