title: Probing the human estrogen receptor-α binding requirements for phenolic mono- and di-hydroxyl compounds: a combined synthesis, binding and docking study.
abstract: Various estrogen analogs were synthesized and tested for binding to human ERα using a fluorescence polarization displacement assay. Binding affinity and orientation were also predicted using docking calculations. Docking was able to accurately predict relative binding affinity and orientation for estradiol, but only if a tightly bound water molecule bridging Arg394/Glu353 is present. Di-hydroxyl compounds sometimes bind in two orientations, which are flipped in terms of relative positioning of their hydroxyl groups. Di-hydroxyl compounds were predicted to bind with their aliphatic hydroxyl group interacting with His524 in ERα. One nonsteroid-based dihdroxyl compound was 1000-fold specific for ERβ over ERα, and was also 25-fold specific for agonist ERβ versus antagonist activity. Docking predictions suggest this specificity may be due to interaction of the aliphatic hydroxyl with His475 in the agonist form of ERβ, versus with Thr299 in the antagonist form. But, the presence of this aliphatic hydroxyl is not required in all compounds, since mono-hydroxyl (phenolic) compounds bind ERα with high affinity, via hydroxyl hydrogen bonding interactions with the ERα Arg394/Glu353/water triad, and van der Waals interactions with the rest of the molecule.
authors: Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, United States; Department of Cancer Systems Imaging, University of Texas-M.D. Anderson Cancer Center, Houston, TX 77030, United States.
authors: Christopher
authors: C
authors: McCullough
authors: Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, United States; School of Pharmacy, Center for Structure-based Drug Design and Development, Concordia University Wisconsin, Mequon, WI 53097, United States.
authors: Terrence S
authors: TS
authors: Neumann
authors: Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, United States; Toronto Research Chemicals Inc., 2 Brisbane Rd., North York, Toronto M3J 2J8, Canada.
authors: Jayapal Reddy
authors: JR
authors: Gone
authors: Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, United States; The State Key Laboratory of Elemento-Organic Chemistry and Department of Chemistry, Nankai University, Tianjin, China.
authors: Zhengjie
authors: Z
authors: He
authors: Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, United States.
authors: Christian
authors: C
authors: Herrild
authors: Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, United States; Division of Natural & Applied Sciences, University of Wisconsin-Green Bay, 2420 Nicolet Drive, Green Bay, WI 54311, United States.
authors: Julie
authors: J
authors: Wondergem Nee Lukesh
authors: Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, United States; AllExcel Inc., 135 Wood Street, West Haven, CT 06516, United States.
authors: Rajesh K
authors: RK
authors: Pandey
authors: Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, United States.
authors: William A
authors: WA
authors: Donaldson
authors: Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, United States; School of Pharmacy, Center for Structure-based Drug Design and Development, Concordia University Wisconsin, Mequon, WI 53097, United States. Electronic address: Daniel.Sem@cuw.edu.
authors: Daniel S
authors: DS
authors: Sem
mesh_terms: D004958:Estradiol / Q000737:chemistry*; D047628:Estrogen Receptor alpha / Q000737:chemistry*; D005260:Female; D006801:Humans; D017665:Hydroxyl Radical / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D017665:Hydroxyl Radical; D004958:Estradiol
keywords: Breast cancer; Docking; Endocrine disruptor; Estrogen receptor; Phenolic