Journal of Molecular Modeling

, 25:278 | Cite as

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

  • Enguang Yu
  • Yueping Xu
  • Yanbo Shi
  • Qiuyan Yu
  • Jie Liu
  • Lei XuEmail author
Original Paper


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.

Graphical abstract



Estrogen receptor (ER) α Traditional Chinese medicine (TCM) Molecular docking Pharmacophore model Molecular dynamics simulation Virtual screening 



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).

Supplementary material

894_2019_4156_MOESM1_ESM.doc (1.1 mb)
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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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Chinese SurgeryJiaxing University Affiliated Jiaxing Hospital of Traditional Chinese MedicineJiaxingPeople’s Republic of China
  2. 2.Department of NursingJiaxing University Affiliated Jiaxing Hospital of Traditional Chinese MedicineJiaxingPeople’s Republic of China
  3. 3.Central Laboratory of Molecular Medicine Research CenterJiaxing University Affiliated Jiaxing Hospital of Traditional Chinese MedicineJiaxingPeople’s Republic of China
  4. 4.Department of Breast SurgeryJiaxing University Affiliated Jiaxing Hospital of Traditional Chinese MedicineJiaxingPeople’s Republic of China
  5. 5.Department of Traditional Chinese Medicine OncologyJiaxing University Affiliated Jiaxing Hospital of Traditional Chinese MedicineJiaxingPeople’s Republic of China
  6. 6.Institute of Bioinformatics and Medical Engineering, School of Electrical and Information EngineeringJiangsu University of TechnologyChangzhouChina

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