Dataset Information

Probing the human estrogen receptor-? 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 ER? 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 ER?. One nonsteroid-based dihdroxyl compound was 1000-fold specific for ER? over ER?, and was also 25-fold specific for agonist ER? versus antagonist activity. Docking predictions suggest this specificity may be due to interaction of the aliphatic hydroxyl with His475 in the agonist form of ER?, 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 ER? with high affinity, via hydroxyl hydrogen bonding interactions with the ER? Arg394/Glu353/water triad, and van der Waals interactions with the rest of the molecule.

SUBMITTER: McCullough C

PROVIDER: S-EPMC4013293 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Probing the human estrogen receptor-α binding requirements for phenolic mono- and di-hydroxyl compounds: a combined synthesis, binding and docking study.

McCullough Christopher C Neumann Terrence S TS Gone Jayapal Reddy JR He Zhengjie Z Herrild Christian C Wondergem Nee Lukesh Julie J Pandey Rajesh K RK Donaldson William A WA Sem Daniel S DS

Bioorganic & medicinal chemistry 20131121 1

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 t ...[more]

PMID: 24315190

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Dataset Information

Probing the human estrogen receptor-? binding requirements for phenolic mono- and di-hydroxyl compounds: a combined synthesis, binding and docking study.

Publications

Probing the human estrogen receptor-α binding requirements for phenolic mono- and di-hydroxyl compounds: a combined synthesis, binding and docking study.

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