Structures of Endocrine-Disrupting Chemicals Determine Binding to and Activation of the Estrogen Receptor α and Androgen Receptor

Endocrine-disrupting chemicals (EDCs)
can interact with nuclear
receptors, including estrogen receptor α (ERα) and androgen
receptor (AR), to affect the normal endocrine system function, causing
severe symptoms. Limited studies queried the EDC mechanisms, focusing
on limited chemicals or a set of structurally similar compounds. It
remained uncertain how hundreds of diverse EDCs could bind to ERα
and AR and cause distinct functional consequences. Here, we employed
a series of computational methodologies to investigate the structural
features of EDCs that bind to and activate ERα and AR based
on more than 4000 compounds. We used molecular docking and molecular
dynamics simulations to elucidate the functional consequences and
validated structure–function correlations experimentally using
a time-resolved fluorescence resonance energy-transfer assay. We found
that EDCs share three levels of key fragments. Primary (20 for ERα
and 18 for AR) and secondary fragments (38 for ERα and 29 for
AR) are responsible for the binding to receptors, and tertiary fragments
determine the activity type (agonist, antagonist, or mixed). In summary,
our study provides a general mechanism for the EDC function. Discovering
the three levels of key fragments may drive fast screening and evaluation
of potential EDCs from large sets of commercially used synthetic compounds.