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Discovery of novel natural compound inhibitors targeting estrogen receptor α by an integrated virtual screening strategy

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Abstract

Estrogen receptor (ER) is a nuclear hormone receptor and plays an important role in mediating the cellular effects of estrogen. ER can be classified into two receptors: estrogen receptor alpha (ERα) and beta (ERβ), and the former is expressed in 50~80% of breast tumors and has been extensively investigated in breast cancer for decades. Excessive exposure to estrogen can obviously stimulate the growth of breast cancers primarily mediated by ERα, and thus anti-estrogen therapies by small molecules are of concern to clinicians and pharmaceutical industry in the treatment of ERα-positive breast cancers. Although a series of estrogen receptor modulators have been developed, these drugs can lead to resistance and side effects. Therefore, the development of small molecule inhibitors with high target specificity has been intensified. In this pursuit, an integrated computer-aided virtual screening technique, including molecular docking and pharmacophore model screening, was used to screen traditional Chinese medicine (TCM) databases. The compounds with high docking scores and fit values were subjected to ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction, and ten hits were identified as potential inhibitors targeting ERα. Molecular docking was used to investigate the binding modes between ERα and three most potent hits, and molecular dynamic simulations were chosen to explore the stability of these complexes. The rank of the predicted binding free energies evaluated by MM/GBSA is consistent with the docking score. These novel scaffolds discovered in the present study can be used as critical starting point in the drug discovery process for treating ERα-positive breast cancer.

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Acknowledgments

This study is supported by the National Science Foundation of China (81803430) and Qing Lan Project and Postgraduate Research and Practice Innovation Program of Jiangsu Province (SJCX18_1051).

Author information

Authors and Affiliations

  1. Department of Chinese Surgery, Jiaxing University Affiliated Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, 314000, Zhejiang, People’s Republic of China

    Enguang Yu

  2. Department of Nursing, Jiaxing University Affiliated Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, 314000, Zhejiang, People’s Republic of China

    Yueping Xu

  3. Central Laboratory of Molecular Medicine Research Center, Jiaxing University Affiliated Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, 314000, Zhejiang, People’s Republic of China

    Yanbo Shi

  4. Department of Breast Surgery, Jiaxing University Affiliated Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, 314000, Zhejiang, People’s Republic of China

    Qiuyan Yu

  5. Department of Traditional Chinese Medicine Oncology, Jiaxing University Affiliated Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, 314000, Zhejiang, People’s Republic of China

    Jie Liu

  6. Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, Jiangsu, China

    Lei Xu

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  1. Enguang Yu
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  6. Lei Xu
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Correspondence to Lei Xu.

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Enguang Yu and Yueping Xu are equivalent authors.

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Figure S1

Superposition of eight crystal bound ligands in the ERα activity site. (a) Eight ligands are displayed in sticks and colored green, blue, turquoise, dark green, yellow, orange, pink and red for different ERα crystal structures (PDB ID: 1ERR, 1SJ0, 1XP1, 2IOG, 3ERT, 5AAU, 5FQP and 6B0F). (b) Proteins are shown with ribbon and colored gray. (DOC 1118 kb)

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Yu, E., Xu, Y., Shi, Y. et al. Discovery of novel natural compound inhibitors targeting estrogen receptor α by an integrated virtual screening strategy. J Mol Model 25, 278 (2019). https://doi.org/10.1007/s00894-019-4156-7

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  • DOI: https://doi.org/10.1007/s00894-019-4156-7

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