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Volume 26
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10.3390/ijms26209878
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Computer-Aided Molecular Design Meets Network Toxicology and Molecular Docking: A Joint Strategy to Explore Common Molecular Mechanisms of Phthalates on Human Breast Cancer and Structure–Activity Relationship

by
Xinyu Yang
1,2,
Zijun Bai
1,
Xiaoyun Yan
1,
Yu Zhou
1,
Caiyun Zhong
1 and
Jieshu Wu
1,*
1
Key Lab of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
2
Department of Stomatology, School of Stomatology, Nanjing Medical University, Nanjing 211166, China
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(20), 9878; https://doi.org/10.3390/ijms26209878
Submission received: 16 September 2025 / Revised: 4 October 2025 / Accepted: 6 October 2025 / Published: 10 October 2025
(This article belongs to the Section Molecular Toxicology)
Versions Notes

Abstract

Distinct PAEs are implicated in breast cancer progression through multiple molecular pathways. This study aims to elucidate the potential mechanisms in common by which PAEs promote breast cancer progression. Dibutyl phthalate (DBP), benzyl butyl phthalate (BBP), and diethylhexyl phthalate (DEHP) were selected as representative PAE compounds. Network toxicology guided the construction of a regulatory network centered on five key transcription factor-associated genes: TP53, CTNNB1, PPARA, ESR1, and CDKN2A. Differential expression and survival analyses confirmed the significant impact of these hub genes on breast cancer (p < 0.05). Molecular docking results revealed direct interactions between the three PAEs and hub targets, while BBP had the strongest PAE-hub gene interaction and DEHP had the weakest one. Computer-aided molecular design (CAMD), combined with molecular docking, found the importance of alkyl chains and phenyl in PAE-hub gene interaction. A group addition/subtraction controlled experiment revealed that the binding affinities of modified BBP variants to hub genes are all weaker than the unmodified parent. The drop was significant whether the C17 alkyl chain was lengthened to match DEHP (p = 0.026) or the phenyl group was removed (p = 0.022). The findings provide novel insights into the mechanism in common of PAE-promoting breast cancer and offer a foundation for the unified intervention strategies and the design of safer plasticizer alternatives.
Keywords: phthalates; breast cancer; common mechanisms; network toxicology; molecular docking; computer-aided molecular design; structure–activity relationship phthalates; breast cancer; common mechanisms; network toxicology; molecular docking; computer-aided molecular design; structure–activity relationship

Share and Cite

MDPI and ACS Style

Yang, X.; Bai, Z.; Yan, X.; Zhou, Y.; Zhong, C.; Wu, J. Computer-Aided Molecular Design Meets Network Toxicology and Molecular Docking: A Joint Strategy to Explore Common Molecular Mechanisms of Phthalates on Human Breast Cancer and Structure–Activity Relationship. Int. J. Mol. Sci. 2025, 26, 9878. https://doi.org/10.3390/ijms26209878

AMA Style

Yang X, Bai Z, Yan X, Zhou Y, Zhong C, Wu J. Computer-Aided Molecular Design Meets Network Toxicology and Molecular Docking: A Joint Strategy to Explore Common Molecular Mechanisms of Phthalates on Human Breast Cancer and Structure–Activity Relationship. International Journal of Molecular Sciences. 2025; 26(20):9878. https://doi.org/10.3390/ijms26209878

Chicago/Turabian Style

Yang, Xinyu, Zijun Bai, Xiaoyun Yan, Yu Zhou, Caiyun Zhong, and Jieshu Wu. 2025. "Computer-Aided Molecular Design Meets Network Toxicology and Molecular Docking: A Joint Strategy to Explore Common Molecular Mechanisms of Phthalates on Human Breast Cancer and Structure–Activity Relationship" International Journal of Molecular Sciences 26, no. 20: 9878. https://doi.org/10.3390/ijms26209878

APA Style

Yang, X., Bai, Z., Yan, X., Zhou, Y., Zhong, C., & Wu, J. (2025). Computer-Aided Molecular Design Meets Network Toxicology and Molecular Docking: A Joint Strategy to Explore Common Molecular Mechanisms of Phthalates on Human Breast Cancer and Structure–Activity Relationship. International Journal of Molecular Sciences, 26(20), 9878. https://doi.org/10.3390/ijms26209878

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