Structures of Endocrine-Disrupting Chemicals Correlate with the Activation of 12 Classic Nuclear Receptors

Endocrine-disrupting chemicals (EDCs)
can inadvertently interact
with 12 classic nuclear receptors (NRs) that disrupt the endocrine
system and cause adverse effects. There is no widely accepted understanding
about what structural features make thousands of EDCs able to activate
different NRs as well as how these structural features exert their
functions and induce different outcomes at the cellular level. This
paper applies the hierarchical characteristic fragment methodology
and high-throughput screening molecular docking to comprehensively
explore the structural and functional features of EDCs for the 12
NRs based on more than 7000 chemicals from curated datasets. EDCs
share three levels of key fragments. The primary and secondary fragments
are associated with the binding of EDCs to four groups of receptors:
steroidal nuclear receptors (SNRs, including androgen, estrogen, glucocorticoid,
mineralocorticoid, and progesterone), retinoic acid receptors, thyroid
hormone receptors, and vitamin D receptors. The tertiary fragments
determine the activity type by interacting with two key locations
in the ligand-binding domains of NRs (N–H5–H3–C
and N–H7–H11–C for SNRs and N–H5–H5′–H2′–H3–C
and N–H6′–H11–C for non-SNRs). The resulting
compiled structural fragments of EDCs together with elucidated compound
NR binding modes provide a framework for understanding the interactions
between EDCs and NRs, facilitating faster and more accurate screening
of EDCs for multiple NRs in the future.