Investigation of the Synergistic Activation of Estrogen Receptors ERα and ERβ by DIBP and MIBP: A Molecular Docking Study Based on AutoDock

Zhijian Wang

doi:10.54254/2755-2721/2025.GL24471

Applied and Computational EngineeringOpen access

Investigation of the Synergistic Activation of Estrogen Receptors ERα and ERβ by DIBP and MIBP: A Molecular Docking Study Based on AutoDock

Research Article

Open Access

Investigation of the Synergistic Activation of Estrogen Receptors ERα and ERβ by DIBP and MIBP: A Molecular Docking Study Based on AutoDock

Zhijian Wang ^1*

¹ College of Resources and Environment, Huazhong Agricultural University, Wuhan, Hubei Province, China 430070

^*Corresponding author: 1261251918@qq.com

Published on 4 July 2025

ACE Vol.172

ISSN (Print): 2755-273X

ISSN (Online): 2755-2721

ISBN (Print): 978-1-80590-221-8

ISBN (Online): 978-1-80590-222-5

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Abstract

This study aims to investigate the synergistic activation effects and molecular mechanisms of diisobutyl phthalate (DIBP) and its metabolite monoisobutyl phthalate (MIBP) on estrogen receptors ERα and ERβ under combined exposure. Using AutoDock 4.2.6, molecular docking of the ligand-binding domains (LBDs) of ERα and ERβ is performed to analyze binding free energy (ΔG), key interaction sites, and spatial complementarity under single and combined treatments. The results show significant synergistic effects of DIBP and MIBP on both ERα and ERβ, which is hypothesized to result from the specific spatial complementarity of DIBP and MIBP in the receptors and the additive effect of binding energies, thereby significantly enhancing their synergistic activation of ERα and ERβ. Overall, DIBP-MIBP preferentially activate ERβ (ΔG=-9.058) more potently than ERα (ΔG=-7.73) through a two-site synergistic mechanism, suggesting that mixed exposure may enhance endocrine-disrupting effects on non-reproductive systems. This highlights the insufficient attention paid to the synergistic effects of PAEs metabolites and provides a basis for establishing receptor subtype-specific exposure limits. Given the scarcity of research on mixed exposure and the incomplete understanding of underlying mechanisms, and because molecular docking results solely reflect receptor binding capacity, the conclusions are inferred from binding energies and require validation by in vitro/in vivo experiments to demonstrate functional effects.

Keywords:

phthalates, estrogen receptors, molecular docking simulation, synergistic effect

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References

[1]. Gao, H. T., Li, R. X., Di, Q. N., Gao, H. W., & Xu, Q. (2017). Exposure levels and health risks of phthalate esters in the Chinese population. Carcinogenesis, Teratogenesis & Mutagenesis, 29(6), 471-475.

[2]. Cleys, P., Panneel, L., Bombeke, J., Dumitrascu, C., Malarvannan, G., Poma, G., ... & Covaci, A. (2023). Hair as an alternative matrix to assess exposure of premature neonates to phthalate and alternative plasticizers in the neonatal intensive care unit. Environmental Research, 236, 116712.

[3]. Zhang, Y., Yang, Y., Tao, Y., Guo, X., Cui, Y., & Li, Z. (2023). Phthalates (PAEs) and reproductive toxicity: Hypothalamic-pituitary-gonadal (HPG) axis aspects. Journal of Hazardous Materials, 459, 132182.

[4]. Zhang, Y., Yuan, Q., Jiang, M., Zheng, L., Sui, Y. M., Wang, Y. L., & Wang, C. H. (2019). Advances in toxicity and detection methods of phthalate esters. Environmental Chemistry, 38(5), 1035-1046.

[5]. Li, Y. H., Lu, J. J., Yin, X. W., Liu, Z. L., Tong, Y. B., & Zhou, L. (2019). Pollution characteristics and infant health risk assessment of phthalate esters in residential environments during heating and non-heating seasons in Shihezi City. Acta Scientiae Circumstantiae, 39(9), 3154-3162. doi: 10.13671/j.hjkxxb.2019.0162

[6]. Koch, H. M., Bolt, H. M., Preuss, R., & Angerer, J. (2005). New metabolites of di (2-ethylhexyl) phthalate (DEHP) in human urine and serum after single oral doses of deuterium-labelled DEHP. Archives of toxicology, 79, 367-376.

[7]. Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of computational chemistry, 30(16), 2785-2791.

[8]. Xie, Z., Zhang, X., Xie, Y., Wu, J., & Wu, Y. (2022). Occurrences and potential lipid-disrupting effects of phthalate metabolites in humpback dolphins from the South China Sea. Journal of Hazardous Materials, 439, 129939.

[9]. Reinhardt Martin & Grubmüller Helmut. (2021). GROMACS implementation of free energy calculations with non-pairwise Variationally derived Intermediates. Computer Physics Communications, 264.

[10]. Shi, S. F., & Yu, C. Q. (2005). Research advances in phytoestrogens and their action targets. Journal of Integrative Medicine, 3(5), 408-410.

[11]. Qi, H. M. (2023). Design and implementation of an FPGA accelerator for AutoDock Vina algorithm based on low-level concurrency. (Master's thesis, Southeast University).

[12]. Pu, S. Y. (2020). Toxic effects of phthalate esters on zebrafish growth, development, and glucose metabolism. (Doctoral dissertation, University of Chinese Academy of Sciences).

[13]. Zhang, Y. H., Xiao, N., & Li, X. Y. (2013). Effects of endocrine disrupting chemicals on estrogen receptor signaling pathways. Journal of Shaanxi Normal University (Natural Science Edition), 41(1), 53-58.

[14]. Zhou, Z., Fan, H., Yu, D., Shi, F., Li, Q., Zhang, Z., ... & Mi, W. (2023). Glutathione-responsive PROTAC for targeted degradation of ERα in breast cancer cells. Bioorganic & Medicinal Chemistry, 96, 117526.

[15]. Ma, L., Wu, Y., Zhou, J., Cheng, C., Li, Y., Yao, Y., & Wu, L. (2023). Multispectral method combined with molecular modelling to investigate the binding mechanisms of DBP and DIBP on pepsin. Journal of Molecular Liquids, 390, 123090.

[16]. Gao, K., Hua, K., Wang, S., Chen, X., & Zhu, T. (2025). Exploring the reproductive exposure risks of phthalates and organophosphates in atmospheric particulate matter based on quantitative structure-activity relationships and network toxicology models. Journal of Hazardous Materials, 137395.

[17]. Qiu, S., Song, M. M., & Liu, C. (2023). Research advances in reproductive toxicity and molecular mechanisms of phthalates. Life Sciences, 35(7), 935-946.

[18]. Zhang, Z. S., & Zhuang, S. L. (2014). Analysis of Differences in Estrogenic Effects of Chlornitrofen-amino Mediated by ERα and ERβ. Journal of Zhejiang University of Technology (Natural Science Edition), 42(3), 53-58.

References

[9]. Reinhardt Martin & Grubmüller Helmut. (2021). GROMACS implementation of free energy calculations with non-pairwise Variationally derived Intermediates. Computer Physics Communications, 264.

[10]. Shi, S. F., & Yu, C. Q. (2005). Research advances in phytoestrogens and their action targets. Journal of Integrative Medicine, 3(5), 408-410.

[11]. Qi, H. M. (2023). Design and implementation of an FPGA accelerator for AutoDock Vina algorithm based on low-level concurrency. (Master's thesis, Southeast University).

[12]. Pu, S. Y. (2020). Toxic effects of phthalate esters on zebrafish growth, development, and glucose metabolism. (Doctoral dissertation, University of Chinese Academy of Sciences).

[17]. Qiu, S., Song, M. M., & Liu, C. (2023). Research advances in reproductive toxicity and molecular mechanisms of phthalates. Life Sciences, 35(7), 935-946.

Cite this article

Wang,Z. (2025). Investigation of the Synergistic Activation of Estrogen Receptors ERα and ERβ by DIBP and MIBP: A Molecular Docking Study Based on AutoDock. Applied and Computational Engineering,172,36-43.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

About volume

Volume title: Proceedings of CONF-FMCE 2025 Symposium: Semantic Communication for Media Compression and Transmission

ISBN: 978-1-80590-221-8(Print) / 978-1-80590-222-5(Online)

Editor: Anil Fernando

Conference website: https://2025.conffmce.org/glasgow.html

Conference date: 24 October 2025

Series: Applied and Computational Engineering

Volume number: Vol.172

ISSN: 2755-2721(Print) / 2755-273X(Online)

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