A Computational-Based Approach to Identify Estrogen Receptor α / β Heterodimer Selective Ligands.

Autor:	Coriano CG; Molecular & Environmental Toxicology Center, Department of Oncology (C.G.C., W.X.), Department of Oncology (C.G.C., F.L., C.K.S., Y.W., W.X.), and Wisconsin Clinical Sciences Center, Department of Biostatistics and Medical Informatics (M.L., M.Y.), University of Wisconsin-Madison, Madison, Wisconsin; and Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, Republic of Korea (Y.L.)., Liu F; Molecular & Environmental Toxicology Center, Department of Oncology (C.G.C., W.X.), Department of Oncology (C.G.C., F.L., C.K.S., Y.W., W.X.), and Wisconsin Clinical Sciences Center, Department of Biostatistics and Medical Informatics (M.L., M.Y.), University of Wisconsin-Madison, Madison, Wisconsin; and Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, Republic of Korea (Y.L.)., Sievers CK; Molecular & Environmental Toxicology Center, Department of Oncology (C.G.C., W.X.), Department of Oncology (C.G.C., F.L., C.K.S., Y.W., W.X.), and Wisconsin Clinical Sciences Center, Department of Biostatistics and Medical Informatics (M.L., M.Y.), University of Wisconsin-Madison, Madison, Wisconsin; and Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, Republic of Korea (Y.L.)., Liang M; Molecular & Environmental Toxicology Center, Department of Oncology (C.G.C., W.X.), Department of Oncology (C.G.C., F.L., C.K.S., Y.W., W.X.), and Wisconsin Clinical Sciences Center, Department of Biostatistics and Medical Informatics (M.L., M.Y.), University of Wisconsin-Madison, Madison, Wisconsin; and Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, Republic of Korea (Y.L.)., Wang Y; Molecular & Environmental Toxicology Center, Department of Oncology (C.G.C., W.X.), Department of Oncology (C.G.C., F.L., C.K.S., Y.W., W.X.), and Wisconsin Clinical Sciences Center, Department of Biostatistics and Medical Informatics (M.L., M.Y.), University of Wisconsin-Madison, Madison, Wisconsin; and Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, Republic of Korea (Y.L.)., Lim Y; Molecular & Environmental Toxicology Center, Department of Oncology (C.G.C., W.X.), Department of Oncology (C.G.C., F.L., C.K.S., Y.W., W.X.), and Wisconsin Clinical Sciences Center, Department of Biostatistics and Medical Informatics (M.L., M.Y.), University of Wisconsin-Madison, Madison, Wisconsin; and Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, Republic of Korea (Y.L.)., Yu M; Molecular & Environmental Toxicology Center, Department of Oncology (C.G.C., W.X.), Department of Oncology (C.G.C., F.L., C.K.S., Y.W., W.X.), and Wisconsin Clinical Sciences Center, Department of Biostatistics and Medical Informatics (M.L., M.Y.), University of Wisconsin-Madison, Madison, Wisconsin; and Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, Republic of Korea (Y.L.)., Xu W; Molecular & Environmental Toxicology Center, Department of Oncology (C.G.C., W.X.), Department of Oncology (C.G.C., F.L., C.K.S., Y.W., W.X.), and Wisconsin Clinical Sciences Center, Department of Biostatistics and Medical Informatics (M.L., M.Y.), University of Wisconsin-Madison, Madison, Wisconsin; and Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, Republic of Korea (Y.L.) wxu@oncology.wisc.edu.
Jazyk:	angličtina
Zdroj:	Molecular pharmacology [Mol Pharmacol] 2018 Mar; Vol. 93 (3), pp. 197-207. Date of Electronic Publication: 2018 Jan 02.
DOI:	10.1124/mol.117.108696
Abstrakt:	The biologic effects of estrogens are transduced by two estrogen receptors (ERs), ER α and ER β , which function in dimer forms. The ER α / α homodimer promotes and the ER β / β inhibits estrogen-dependent growth of mammary epithelial cells; the functions of ER α / β heterodimers remain elusive. Using compounds that promote ER α / β heterodimerization, we have previously shown that ER α / β heterodimers appeared to inhibit tumor cell growth and migration in vitro. Further dissection of ER α / β heterodimer functions was hampered by the lack of ER α / β heterodimer-specific ligands. Herein, we report a multistep workflow to identify the selective ER α / 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 ER α / β heterodimer specificity. The pharmacophore encompassing seven features that are potentially important for the formation of the ER α / β heterodimer was retrieved and subsequently used for virtual screening of large chemical libraries. Four chemical compounds were identified that selectively induce ER α / β heterodimers over their respective homodimers. Such ligands will become unique tools to reveal the functional insights of ER α / β heterodimers. (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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