RT Journal Article
SR Electronic
T1 A computational based approach to identify estrogen receptor alpha/beta heterodimer selective ligands
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.117.108696
DO 10.1124/mol.117.108696
A1 Carlos Coriano
A1 Fabao Liu
A1 Chelsie Sievers
A1 Muxuan Liang
A1 Yidan Wang
A1 Yoongho Lim
A1 Menggang Yu
A1 Wei Xu
YR 2018
UL http://molpharm.aspetjournals.org/content/early/2018/01/02/mol.117.108696.abstract
AB The biological 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 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 reported 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 Bioluminescent Resonance Energy Transfer Assay (BRET). 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.