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

Haoyue Tan1, Qinchang Chen1, Huixiao Hong2

  • 1State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University, 210023 Nanjing, China.

Environmental Science & Technology
|December 3, 2021
PubMed

Insights

This study identifies key structural fragments in endocrine-disrupting chemicals (EDCs) that interact with nuclear receptors (NRs). Understanding these fragments aids in predicting and screening EDCs

Area of Science:

  • Environmental Toxicology
  • Molecular Pharmacology
  • Computational Chemistry

Background:

  • Endocrine-disrupting chemicals (EDCs) interfere with the endocrine system by interacting with nuclear receptors (NRs).
  • A comprehensive understanding of the structural features driving EDC-NR interactions and their functional outcomes is lacking.
  • Thousands of EDCs exist, necessitating efficient methods for assessing their potential to activate diverse NRs.

Purpose of the Study:

  • To comprehensively explore the structural and functional features of EDCs responsible for activating 12 classic nuclear receptors (NRs).
  • To establish a framework for understanding EDC-NR interactions and facilitate future screening.
  • To elucidate the specific chemical fragments and binding modes involved in EDC-NR interactions.

Main Methods:

  • Application of the hierarchical characteristic fragment methodology.
  • Utilizing high-throughput screening molecular docking.
  • Analysis of over 7000 chemicals from curated datasets.

Main Results:

  • EDCs were found to share three hierarchical levels of key structural fragments.
  • Primary and secondary fragments correlate with EDC binding to four major NR groups: steroidal nuclear receptors (SNRs), retinoic acid receptors, thyroid hormone receptors, and vitamin D receptors.
  • Tertiary fragments dictate activity type by interacting with specific ligand-binding domain locations within NRs, differentiating between SNRs and non-SNRs.

Conclusions:

  • The identified structural fragments and binding modes provide a foundational understanding of EDC-NR interactions.
  • This framework enables faster and more accurate screening of EDCs for multiple NRs.
  • The study contributes to predicting the adverse effects of EDCs on the endocrine system.
Keywords:
endocrine-disrupting chemicalshierarchical characteristic fragmentmolecular dockingnuclear receptorvirtual screening

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