Evaluation of 17α-E-(trifluoromethylphenyl)vinyl estradiols as novel estrogen receptor ligands

Hanson, Robert N.; Lee, Choon Young; Friel, Carolyn J.; Hughes, Alun; DeSombre, Eugene R.

doi:10.1016/s0039-128x(02)00165-4

Cited by 18 publications

(22 citation statements)

References 31 publications

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“…However, the observed RBA was comparable with E2 with 17α-etinyl group that increases log P C by 0.08 corresponding to 2-fold increase in RBA. Possible explanation of this discrepancy between estimated and observed binding affinities is remodeling of H7 into an extended conformation for the accommodation of the bulky trifluoromethylphenylvinyl group [41] that likely destabilizes the protein structure. Comparison of these results with the prediction results based on docked conformations showed that the misidentification of hydrogen bonds (17α E2) and overestimation of log P C (ethinyl E2), due to the incorrect protein-ligand complex structure, resulted in significant prediction error.…”

Section: Discussionmentioning

confidence: 99%

Structure-Based Understanding of Binding Affinity and Mode of Estrogen Receptor α Agonists and Antagonists

Lee

Barron

2017

PLoS ONE

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The flexible hydrophobic ligand binding pocket (LBP) of estrogen receptor α (ERα) allows the binding of a wide variety of endocrine disruptors. Upon ligand binding, the LBP reshapes around the contours of the ligand and stabilizes the complex by complementary hydrophobic interactions and specific hydrogen bonds with the ligand. Here we present a framework for quantitative analysis of the steric and electronic features of the human ERα-ligand complex using three dimensional (3D) protein-ligand interaction description combined with 3D-QSAR approach. An empirical hydrophobicity density field is applied to account for hydrophobic contacts of ligand within the LBP. The obtained 3D-QSAR model revealed that hydrophobic contacts primarily determine binding affinity and govern binding mode with hydrogen bonds. Several residues of the LBP appear to be quite flexible and adopt a spectrum of conformations in various ERα-ligand complexes, in particular His524. The 3D-QSAR was combined with molecular docking based on three receptor conformations to accommodate receptor flexibility. The model indicates that the dynamic character of the LBP allows accommodation and stable binding of structurally diverse ligands, and proper representation of the protein flexibility is critical for reasonable description of binding of the ligands. Our results provide a quantitative and mechanistic understanding of binding affinity and mode of ERα agonists and antagonists that may be applicable to other nuclear receptors.

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Section: Discussionmentioning

confidence: 99%

Structure-Based Understanding of Binding Affinity and Mode of Estrogen Receptor α Agonists and Antagonists

Lee

Barron

2017

PLoS ONE

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“…This compound binds even more tightly to the hERa than the natural ligand E 2, [28] which is probablyaresult of the increased number of hydrophobic contacts. Increased affinity due to extra hydrogen bonds between fluorinea nd the hydrophilic amino acids in the ligand binding cavity is not likely because the fluorine atomsa ttachedt ot he end of the hydrophobic chain are very weak hydrogen bond acceptors [29] (partial charge À0.34) and the distance between the fluorine atoms and the hydrophilic amino acids is quite large (3.6 ).…”

Section: Influence Of the Hydrophobic Pocket (Site 2)mentioning

confidence: 98%

Involvement of a Hydrophobic Pocket and Helix 11 in Determining the Modes of Action of Prenylated Flavonoids and Isoflavonoids in the Human Estrogen Receptor

Schans

Ritschel

Bovee³

et al. 2015

ChemBioChem

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Six prenylated (iso)flavonoids were purified from a licorice root extract and subjected to competition experiments with six commercially available (iso)flavonoids. The agonistic and antagonistic activities of these compounds towards both hERα (human estrogen receptor alpha) and hERβ were determined. Differences in the modes of action (agonist or antagonist) were observed for the various compounds tested. In general, each compound had the same mode of action towards both ERs. In silico modeling was performed in order to study the differences in estrogenicity observed between the compounds. It is suggested that prenyl chains fit into a hydrophobic pocket present in the hER, resulting in an increased agonistic activity. In addition, it was shown that an increase in length (≈1.7 Å) of pyran prenylated isoflavonoids resulted in an antagonistic mode of action. This might be caused by collision of the pyran ring with helix 11 in the ligand binding cavity of the hER.

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“…This trend is similar to that previously observed for the mono-trifluoromethylated series. [7] Introduction of a second methyl group onto the phenylvinyl moiety expanded the range of RBA values for the series and identified the influence of the second substituent. For example, 2-(ortho)-substitution was still optimal but the highest affinity was observed for those compounds in which the second methyl group was either in the 5-(meta)- (RBA = 37) or 4-(para)- position (RBA = 20.5).…”

Section: Resultsmentioning

confidence: 99%

“…[6] Subsequent examination of the E-(2-,3-, and 4-trifluoromethylphenyl)vinyl estradiols demonstrated significant dependence on substitution patterns, as the 2-isomer was more potent in vitro as well as in vivo . [7] Introduction of an 11β-methoxy group into the E-(2-,3-, and 4-trifluoromethylphenyl)vinyl estradiols had little effect on the affinity for the ER-LBD, however, it provided a significant enhancement of in vivo potency. [8] In parallel with biological assays, we used computational and crystallographic methods to evaluate the results.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of 17α-(dimethylphenyl)vinyl estradiols as probes of the estrogen receptor-α ligand binding domain

et al. 2012

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As part of our program to explore the influence of small structural modifications on the biological response of the estrogen receptor-α (ERα), we prepared and evaluated a series of mono-and di-substituted phenyl vinyl estradiols. The target compounds were prepared in 45 -80 % yields using the Stille coupling reaction and evaluated using competitive binding analysis with the ERα-ligand binding domain (hERα-LBD) and estrogenic activity (induction of alkaline phosphatase in Ishikawa cells). Results indicated that the 2,4- and 2,5-dimethyl derivatives, 5b and 5c, had the highest relative binding affinity (RBA= 20.5 and 37.3%) and relative stimulatory activity (RSA = 101.0 and 12.3%) of the di-methyl series.

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Evaluation of 17α-E-(trifluoromethylphenyl)vinyl estradiols as novel estrogen receptor ligands

Cited by 18 publications

References 31 publications

Structure-Based Understanding of Binding Affinity and Mode of Estrogen Receptor α Agonists and Antagonists

Structure-Based Understanding of Binding Affinity and Mode of Estrogen Receptor α Agonists and Antagonists

Involvement of a Hydrophobic Pocket and Helix 11 in Determining the Modes of Action of Prenylated Flavonoids and Isoflavonoids in the Human Estrogen Receptor

Synthesis and evaluation of 17α-(dimethylphenyl)vinyl estradiols as probes of the estrogen receptor-α ligand binding domain

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