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.

A–C Estrogens as Potent and Selective Estrogen Receptor-Beta Agonists (SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions

“…Recently, we reported a novel ERβ agonist that was more selective for ERβ versus ERα activation than previously reported clinical candidates. (19) This ERβ agonist was in a unique structural class, comprising a phenol ring tethered to a 4-hydroxymethyl-cycloheptane ring system. However, the presence of the 4-substituted cycloheptane ring presents synthetic and stereochemistry challenges, making it less desirable as a drug lead.…”

Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens

“…They include 17β-hydroxysteroid dehydrogenase [ 60 ], progesterone receptor [ 61 ], protein disulfide isomerase [ 62 ], SHBG [ 63 ], CYP1B1 [ 64 ], steroid sulfatase [ 65 ], and even the voltage- and Ca 2+ -activated K + channel β1 subunit [ 66 ]. In all studies, an emphasis is put on the importance of OH-hydrogen binding [ 67 , 68 ]. The relevance of this emphasis is confirmed by experimental results.…”

“…The relevance of this emphasis is confirmed by experimental results. One example is a study where the estrogen analog with the highest affinity, measured in a fluorescence polarization displacement assay, appears to have the second highest predicted affinity [ 67 ].…”

Synthesis and evaluation of 4-cycloheptylphenols as selective Estrogen receptor-β agonists (SERBAs)

“…We have previously reported the synthesis of cis-4-(4-hydroxyphenyl)cycloheptanemethanol (±)-2 from furan (10 steps, 1.9% overall yield, Scheme 1) [14,15]. Evaluation of (±)-2 in cell-based assays revealed a potent and highly selective ERβ agonist.…”

“…We herein report alternative syntheses of 2, which result in the preparation of a racemic mixture of four stereoisomers, the separation of these stereoisomers and structural characterization of two of the enantiomeric structures, and the evaluation of the four stereoisomers as ERβ ligands, and promising ERβ agonist therapeutic lead molecules. (refs. [ [14], [15]]).…”