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

Bioorg Med Chem. 2014 Jan 1;22(1):303-10. doi: 10.1016/j.bmc.2013.11.024. Epub 2013 Nov 21.

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.

Keywords: Breast cancer; Docking; Endocrine disruptor; Estrogen receptor; Phenolic.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Estradiol / chemistry*
  • Estrogen Receptor alpha / chemistry*
  • Female
  • Humans
  • Hydroxyl Radical / chemical synthesis*
  • Hydroxyl Radical / chemistry
  • Structure-Activity Relationship

Substances

  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Hydroxyl Radical
  • Estradiol