Allosteric binding on nuclear receptors: Insights on screening of non-competitive endocrine-disrupting chemicals

Zhang, Chi; Wu, Jinqiu; Chen, Qinchang; Tan, Haoyue; Huang, Fuyan; Guo, Jing; Zhang, Xiaowei; H, Yu; Shi, Wei

doi:10.1016/j.envint.2021.107009

Cited by 8 publications

(10 citation statements)

References 213 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We found that 86% of androgens and estrogens competitively bind to AR and ERs; only 36% of anti-androgens were positive in the ligand-receptor binding process; 82% of negative compounds did not have competitive binding activity. The divergence between agonists and antagonists in the ligand-receptor binding process follows previous studies . Unlike agonistic activity produced by binding to the orthosteric site of NRs (AR and ER LBDs), a part of antagonistic activities can be produced by binding to allosteric sites of NRs …”

Section: Resultsmentioning

confidence: 69%

“…The divergence between agonists and antagonists in the ligandreceptor binding process follows previous studies. 83 Unlike agonistic activity produced by binding to the orthosteric site of NRs (AR and ER LBDs), a part of antagonistic activities can be produced by binding to allosteric sites of NRs. 83 Moreover, the AOP-based prediction model can also resist the biological noise of in vitro assays.…”

Section: Curation Of Heterogeneous In Vitro and In Vivo Datamentioning

confidence: 99%

“…83 Unlike agonistic activity produced by binding to the orthosteric site of NRs (AR and ER LBDs), a part of antagonistic activities can be produced by binding to allosteric sites of NRs. 83 Moreover, the AOP-based prediction model can also resist the biological noise of in vitro assays. For example, KE4 (gene expression) in AR-mediated AOP was measured by three reporter gene assays.…”

Section: Curation Of Heterogeneous In Vitro and In Vivo Datamentioning

confidence: 99%

See 2 more Smart Citations

Development, Validation, and Application of a Human Reproductive Toxicity Prediction Model Based on Adverse Outcome Pathway

Tan

Zhang

et al. 2022

Environ. Sci. Technol.

Self Cite

View full text Add to dashboard Cite

A growing number of environmental contaminants have been proved to have reproductive toxicity to males and females. However, the unclear toxicological mechanism of reproductive toxicants limits the development of virtual screening methods. By consolidating androgen (AR)-/estrogen receptors (ERs)-mediated adverse outcome pathways (AOPs) with more than 8000 chemical substances, we uncovered relationships between chemical features, a series of pathway-related effects, and reproductive apical outcomeschanges in sex organ weights. An AOP-based computational model named RepTox was developed and evaluated to predict and characterize chemicals’ reproductive toxicity for males and females. Results showed that RepTox has three outstanding advantages. (I) Compared with the traditional models (37 and 81% accuracy, respectively), AOP significantly improved the predictive robustness of RepTox (96.3% accuracy). (II) Compared with the application domain (AD) of models based on small in vivo datasets, AOP expanded the ADs of RepTox by 1.65-fold for male and 3.77-fold for female, respectively. (III) RepTox implied that hydrophobicity, cyclopentanol substructure, and several topological indices (e.g., hydrogen-bond acceptors) were important, unbiased features associated with reproductive toxicants. Finally, RepTox was applied to the inventory of existing chemical substances of China and identified 2100 and 7281 potential toxicants to the male and female reproductive systems, respectively.

show abstract

Section: Resultsmentioning

confidence: 69%

Section: Curation Of Heterogeneous In Vitro and In Vivo Datamentioning

confidence: 99%

Section: Curation Of Heterogeneous In Vitro and In Vivo Datamentioning

confidence: 99%

See 1 more Smart Citation

Development, Validation, and Application of a Human Reproductive Toxicity Prediction Model Based on Adverse Outcome Pathway

Tan

Zhang

et al. 2022

Environ. Sci. Technol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Compared to NRs, which are transcription factors [ 4 ], MbRs exert acute short-term responses even when they ultimately stimulate gene transcription. Considering the classical definitions of EDs [ 5 , 6 , 7 , 8 ], there is no theoretical impeachment for MbRs to be ED targets.…”

Section: Introductionmentioning

confidence: 99%

Membrane Hormone Receptors and Their Signaling Pathways as Targets for Endocrine Disruptors

Combarnous

Nguyen

2022

JoX

View full text Add to dashboard Cite

The endocrine disruptors are mostly small organic molecules developed for numerous and very diverse industrial applications. They essentially act through nuclear receptors with small and hydrophobic endogenous ligands. Nevertheless, potential adverse effects through membrane hormone receptors cannot be ruled out, and have indeed been observed. The present paper reviews how orthosteric and allosteric binding sites of the different families of membrane receptors can be targets for man-made hydrophobic molecules (components of plastics, paints, flame retardants, herbicides, pesticides, etc.). We also review potential target proteins for such small hydrophobic molecules downstream of membrane receptors at the level of their intracellular signaling pathways. From the currently available information, although endocrine disruptors primarily affect nuclear receptors’ signaling, membrane receptors for hormones, cytokines, neuro-mediators, and growth factors can be affected as well and deserve attention.

show abstract

“…Another way of bypassing the characteristic mutation-driven resistance of conventional anti-androgens that has been explored is targeting alternative drug target sites on the AR. [ 36 , 37 , 38 ]. The activation function-2 (AF2) and binding function-3 (BF3) sites in the LBD have been evaluated for new small-molecule AR inhibitors which affect co-regulator binding [ 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Study to Overcome Cross-Reactivity of Novel Androgen Receptor Inhibitors

Radaeva

Leblanc

et al. 2022

Cells

View full text Add to dashboard Cite

The mutation-driven transformation of clinical anti-androgen drugs into agonists of the human androgen receptor (AR) represents a major challenge for the treatment of prostate cancer patients. To address this challenge, we have developed a novel class of inhibitors targeting the DNA-binding domain (DBD) of the receptor, which is distanced from the androgen binding site (ABS) targeted by all conventional anti-AR drugs and prone to resistant mutations. While many members of the developed 4-(4-phenylthiazol-2-yl)morpholine series of AR-DBD inhibitors demonstrated the effective suppression of wild-type AR, a few represented by 4-(4-(3-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholine (VPC14368) exhibited a partial agonistic effect toward the mutated T878A form of the receptor, implying their cross-interaction with the AR ABS. To study the molecular basis of the observed cross-reactivity, we co-crystallized the T878A mutated form of the AR ligand binding domain (LBD) with a bound VPC14368 molecule. Computational modelling revealed that helix 12 of AR undergoes a characteristic shift upon VPC14368 binding causing the agonistic behaviour. Based on the obtained structural data we then designed derivatives of VPC14368 to successfully eliminate the cross-reactivity towards the AR ABS, while maintaining significant anti-AR DBD potency.

show abstract

Allosteric binding on nuclear receptors: Insights on screening of non-competitive endocrine-disrupting chemicals

Cited by 8 publications

References 213 publications

Development, Validation, and Application of a Human Reproductive Toxicity Prediction Model Based on Adverse Outcome Pathway

Development, Validation, and Application of a Human Reproductive Toxicity Prediction Model Based on Adverse Outcome Pathway

Membrane Hormone Receptors and Their Signaling Pathways as Targets for Endocrine Disruptors

Structure-Based Study to Overcome Cross-Reactivity of Novel Androgen Receptor Inhibitors

Contact Info

Product

Resources

About