A Computational-Based Approach to Identify Estrogen Receptor α/β Heterodimer Selective Ligands
| Autor: | Menggang Yu, Fabao Liu, Chelsie K. Sievers, Muxuan Liang, Wei Xu, Yidan Wang, Yoongho Lim, Carlos G. Coriano |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Bioluminescence Resonance Energy Transfer Techniques
Models Molecular 0301 basic medicine In silico Drug Evaluation Preclinical Estrogen receptor Phytoestrogens Ligands Cell Line 03 medical and health sciences 0302 clinical medicine Estrogen Receptor beta Humans Mammary Glands Human Estrogen receptor beta Pharmacology Virtual screening Chemistry HEK 293 cells Estrogen Receptor alpha Computational Biology Articles Cell biology HEK293 Cells 030104 developmental biology Cell culture 030220 oncology & carcinogenesis MCF-7 Cells Molecular Medicine Female Protein Multimerization Pharmacophore Estrogen receptor alpha |
| Zdroj: | Molecular Pharmacology. 93:197-207 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.117.108696 |
| Popis: | The biologic effects of estrogens are transduced by two estrogen receptors (ERs), ERα and ERβ, which function in dimer forms. The ERα/α homodimer promotes and the ERβ/β inhibits estrogen-dependent growth of mammary epithelial cells; the functions of ERα/β heterodimers remain elusive. Using compounds that promote ERα/β heterodimerization, we have previously shown that ERα/β heterodimers appeared to inhibit tumor cell growth and migration in vitro. Further dissection of ERα/β heterodimer functions was hampered by the lack of ERα/β heterodimer-specific ligands. Herein, we report a multistep workflow to identify the selective ERα/β heterodimer-inducing compound. Phytoestrogenic compounds were first screened for ER transcriptional activity using reporter assays and ER dimerization preference using a bioluminescence resonance energy transfer assay. The top hits were subjected to in silico modeling to identify the pharmacophore that confers ERα/β heterodimer specificity. The pharmacophore encompassing seven features that are potentially important for the formation of the ERα/β heterodimer was retrieved and subsequently used for virtual screening of large chemical libraries. Four chemical compounds were identified that selectively induce ERα/β heterodimers over their respective homodimers. Such ligands will become unique tools to reveal the functional insights of ERα/β heterodimers. |
| Databáze: | OpenAIRE |
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