Discovery of estrogen receptor modulators: a review of virtual screening and SAR efforts

Xue, Xu; Yang, Wei; Li, Yan; Wang, Yonghua

doi:10.1517/17460440903490395

Cited by 16 publications

(9 citation statements)

References 55 publications

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“…For example, ERα is more prevalent in the gonads, mammary glands, kidneys and bronchi, and it stimulates proliferative processes in cells. In turn, ERβ is predominant in bones and pulmonary alveoli, and it delivers antiproliferative effects ( 12 , 13 ). Unlike other steroid receptors, ERs bind to a wide range of exogeneous compounds, and are they are increasingly often classified as promiscuous receptors ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

The Effect of 42-Day Exposure to a Low Deoxynivalenol Dose on the Immunohistochemical Expression of Intestinal ERs and the Activation of CYP1A1 and GSTP1 Genes in the Large Intestine of Pre-pubertal Gilts

et al. 2021

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Deoxynivalenol (DON) is a mycotoxin that contaminates various plant materials. Exposure to DON can disrupt hormonal homeostasis, decrease body weight gains and modulate the immune system in pigs. It can also cause diarrhea, vomiting, leukocytosis, hemorrhaging or even death. Prolonged exposure to low doses of DON can have serious health implications in mammals. This is the first in vivo study to show that per os administration of low DON doses probably contributes to specific dysfunctions in steroidogenesis processes by inducing the immunohistochemical expression of estrogen receptors alpha (ERα) in the entire gastrointestinal tract in strongly stained cells (3 points) and estrogen receptors beta (ERβ), but only in both investigated segments of the duodenum in pre-pubertal gilts. Therefore, the aim of this study was to determine whether a NOAEL dose of DON (12 μg DON/kg BW) administered per os over a period of 42 days induces changes in the immunohistochemical expression of ER in different intestinal segments and the transcriptional activation of CYP1A1 and GSTP1 genes in the large intestine of pre-pubertal gilts. This is the first report to demonstrate the expression of ER, in particular ERβ, with the associated consequences. The expression of ER was accompanied by considerable variations in the activation of CYP1A1 and GSTP1 genes, but it supported the maintenance of a stable consensus between the degree of mycotoxin exposure and the detoxifying effect in pre-pubertal gilts.

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Section: Introductionmentioning

confidence: 99%

The Effect of 42-Day Exposure to a Low Deoxynivalenol Dose on the Immunohistochemical Expression of Intestinal ERs and the Activation of CYP1A1 and GSTP1 Genes in the Large Intestine of Pre-pubertal Gilts

et al. 2021

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“…Since compounds already confirmed by experimental assays provide an opportunity to understand the basis of subtype selectivity, the development of models for predicting the subtype selectivity would allow for the development of more potent and selective compounds for these important pharmaceutical targets. In this context, QSARs can be of valuable assistance in predicting the estrogenic activity of certain molecules [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

In Silico Prediction of Estrogen Receptor Subtype Binding Affinity and Selectivity Using Statistical Methods and Molecular Docking with 2-Arylnaphthalenes and 2-Arylquinolines

Wang

et al. 2010

IJMS

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Over the years development of selective estrogen receptor (ER) ligands has been of great concern to researchers involved in the chemistry and pharmacology of anticancer drugs, resulting in numerous synthesized selective ER subtype inhibitors. In this work, a data set of 82 ER ligands with ERα and ERβ inhibitory activities was built, and quantitative structure-activity relationship (QSAR) methods based on the two linear (multiple linear regression, MLR, partial least squares regression, PLSR) and a nonlinear statistical method (Bayesian regularized neural network, BRNN) were applied to investigate the potential relationship of molecular structural features related to the activity and selectivity of these ligands. For ERα and ERβ, the performances of the MLR and PLSR models are superior to the BRNN model, giving more reasonable statistical properties (ERα: for MLR, Rtr2 = 0.72, Qte2 = 0.63; for PLSR, Rtr2 = 0.92, Qte2 = 0.84. ERβ: for MLR, Rtr2 = 0.75, Qte2 = 0.75; for PLSR, Rtr2 = 0.98, Qte2 = 0.80). The MLR method is also more powerful than other two methods for generating the subtype selectivity models, resulting in Rtr2 = 0.74 and Qte2 = 0.80. In addition, the molecular docking method was also used to explore the possible binding modes of the ligands and a relationship between the 3D-binding modes and the 2D-molecular structural features of ligands was further explored. The results show that the binding affinity strength for both ERα and ERβ is more correlated with the atom fragment type, polarity, electronegativites and hydrophobicity. The substitutent in position 8 of the naphthalene or the quinoline plane and the space orientation of these two planes contribute the most to the subtype selectivity on the basis of similar hydrogen bond interactions between binding ligands and both ER subtypes. The QSAR models built together with the docking procedure should be of great advantage for screening and designing ER ligands with improved affinity and subtype selectivity property.

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“…The ERα and ERβ subtypes are coded by different genes, ESR1 and ESR2 respectively, and are distributed and play multiple roles in a tissue-dependent manner. For example, the ERα is more prevalent in the gonads, mammary glands, kidney and lung bronchi, while ERβ predominates in bone, lung alveoli and prostate tissues [ 5 , 13 , 14 ]; furthermore, ERα has been found to promote cell proliferation while ERβ possesses an anti-proliferative effect in the mammary tissues [ 15 , 16 , 17 ]. The ERα and ERβ appear to share a modest 47% [ 10 , 18 ] and 56% [ 5 ], respectively, overall and ligand binding domain (LBD) sequence identity; yet, only two residues among those that line the binding pocket are found to be different: Leu384 (ERα) vs. Met336 (ERβ) and Met421(ERα) vs. Ile373 (ERβ) [ 5 ] ( Figure 2 ).…”

Section: The Estrogen Receptorsmentioning

confidence: 99%

Versatility or Promiscuity: The Estrogen Receptors, Control of Ligand Selectivity and an Update on Subtype Selective Ligands

Perkins

Tong

et al. 2014

IJERPH

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The estrogen receptors (ERs) are a group of versatile receptors. They regulate an enormity of processes starting in early life and continuing through sexual reproduction, development, and end of life. This review provides a background and structural perspective for the ERs as part of the nuclear receptor superfamily and discusses the ER versatility and promiscuity. The wide repertoire of ER actions is mediated mostly through ligand-activated transcription factors and many DNA response elements in most tissues and organs. Their versatility, however, comes with the drawback of promiscuous interactions with structurally diverse exogenous chemicals with potential for a wide range of adverse health outcomes. Even when interacting with endogenous hormones, ER actions can have adverse effects in disease progression. Finally, how nature controls ER specificity and how the subtle differences in receptor subtypes are exploited in pharmaceutical design to achieve binding specificity and subtype selectivity for desired biological response are discussed. The intent of this review is to complement the large body of literature with emphasis on most recent developments in selective ER ligands.

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Discovery of estrogen receptor modulators: a review of virtual screening and SAR efforts

Abstract: With the goal of reducing toxicity and/or improving efficacy, challenges to the successful modeling of endocrine agents are proposed, providing new paradigms for the design of ER inhibitors.

Cited by 16 publications

References 55 publications

The Effect of 42-Day Exposure to a Low Deoxynivalenol Dose on the Immunohistochemical Expression of Intestinal ERs and the Activation of CYP1A1 and GSTP1 Genes in the Large Intestine of Pre-pubertal Gilts

The Effect of 42-Day Exposure to a Low Deoxynivalenol Dose on the Immunohistochemical Expression of Intestinal ERs and the Activation of CYP1A1 and GSTP1 Genes in the Large Intestine of Pre-pubertal Gilts

In Silico Prediction of Estrogen Receptor Subtype Binding Affinity and Selectivity Using Statistical Methods and Molecular Docking with 2-Arylnaphthalenes and 2-Arylquinolines

Versatility or Promiscuity: The Estrogen Receptors, Control of Ligand Selectivity and an Update on Subtype Selective Ligands

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