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Tan H, Chen Q, Hong H, et al. Structures of Endocrine-Disrupting Chemicals Correlate with the Activation of 12 Classic Nuclear Receptors. Environ Sci Technol. 2021;55(24):16552-16562doi: 10.1021/acs.est.1c04997.
Tan, H., Chen, Q., Hong, H., Benfenati, E., Gini, G. C., Zhang, X., Yu, H., & Shi, W. (2021). Structures of Endocrine-Disrupting Chemicals Correlate with the Activation of 12 Classic Nuclear Receptors. Environmental science & technology, 55(24), 16552-16562. https://doi.org/10.1021/acs.est.1c04997
Tan, Haoyue, et al. "Structures of Endocrine-Disrupting Chemicals Correlate with the Activation of 12 Classic Nuclear Receptors." Environmental science & technology vol. 55,24 (2021): 16552-16562. doi: https://doi.org/10.1021/acs.est.1c04997
Tan H, Chen Q, Hong H, Benfenati E, Gini GC, Zhang X, Yu H, Shi W. Structures of Endocrine-Disrupting Chemicals Correlate with the Activation of 12 Classic Nuclear Receptors. Environ Sci Technol. 2021 Dec 21;55(24):16552-16562. doi: 10.1021/acs.est.1c04997. Epub 2021 Dec 03. PMID: 34859678.
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Environ Sci Technol. 2021 Dec 21;55(24):16552-16562. doi: 10.1021/acs.est.1c04997. Epub 2021 Dec 03.

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

Environmental science & technology

Haoyue Tan, Qinchang Chen, Huixiao Hong, Emilio Benfenati, Giuseppina C Gini, Xiaowei Zhang, Hongxia Yu, Wei Shi

Affiliations

  1. State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University, 210023 Nanjing, China.
  2. National Center for Toxicological Research, U. S. Food and Drug Administration, 3900 NCTR Road., Jefferson, Arkansas 72079, United States.
  3. Laboratory of Environmental Chemistry and Toxicology, Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy.
  4. Department of Electronics and Information, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milan, Italy.

PMID: 34859678 DOI: 10.1021/acs.est.1c04997

Abstract

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.

Keywords: endocrine-disrupting chemicals; hierarchical characteristic fragment; molecular docking; nuclear receptor; virtual screening

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