The estrogen receptor and polyphenols: molecular simulation studies of their interactions, a review

Abstract

Estrogens exert their physiological effects by binding to the estrogen receptor (ER), a ligand-activated transcription factor, of the nuclear receptors' family. All ER ligands bind exclusively to the ligand-binding domain (LBD) of the receptor. A number of crystallographic studies have shown that the position of the C-terminal Helix of ER LBD (Helix-12) can be associated to the agonist, antagonist, or partial agonist activity of a ligand.Molecular simulations presented in this work can be used as a tool in the prediction of activity of ER ligands and the investigation of the conformational changes induced by these ligands on LBD in order to design new selective estrogen receptor modulators (SERMs).Docking calculations that were performed using the low frequency mode (LMOD) conformational search could very well simulate the crystallographic results. The treatment of the water molecule in the Ligand Binding Pocket and the method for calculating atomic charges was found to be critical for deriving low energy structures.In order to predict binding affinities a computational model was constructed relating calculated energy terms to binding affinities for a series of polyphenolic phytoestrogens. A satisfying correlation was obtained by linear regression between experimental and predicted binding affinities. The relative orientation of the ligands in the binding cavity gives an insight of the interactions Finally, we examined the LBD conformational changes based on the recent crystallographic structures. Our results show that application of the LMOD calculation procedure enables the prediction of the agonist-antagonist activity of different ligands based on the position of Helix-12.

Estrogenic activity of isoflavonoids from the stem bark of the tropical tree Amphimas pterocarpoides , a source of traditional medicines

“…ERa and ERb are known to bind phenols possessing two hydroxyl groups with an OÀ ÀO distance of 9.7-12.3 Å [13]. Isoflavonoids 3 (11.92 Å) and 6 (11.89 Å) and the R (11.79 Å) and S (9.85 Å) configurations of 4 fulfill this requirement.…”

“…Isoflavonoids 3 (11.92 Å) and 6 (11.89 Å) and the R (11.79 Å) and S (9.85 Å) configurations of 4 fulfill this requirement. There are at least two major positions of the C-terminal helix 12 of ERa and ERb, depending on whether the receptor is bound to an agonist or an antagonist [13,47]. Equilibrium has been proposed to exist between the agonist-bound and the antagonist-bound conformations of helix 12 [47].…”

“…Phytoestrogens are plantderived polyphenols that in the majority of cases bind preferentially to ERb and produce tissue-, cell-and gene promoter-specific effects partly similar to estrogen [10][11][12][13]. Recent studies have shown that ERb-selective phytoestrogens tend to regulate apoptotic rather than proliferative genes; and that the potency and efficacy of ERb-dependent regulation of gene expression by phytoestrogens may far exceed predictions based on ERb-binding affinity [10,11].…”

Estrogenic properties of naturally occurring prenylated isoflavones in U2OS human osteosarcoma cells: Structure–activity relationships

“…Specifically, much attention has been given to soy isoflavones including genistein (4 ,5,7-trihydroxyisoflavone) which is a widespread isoflavone in plants belonging to the Leguminosae family, and is well known for its estrogenic properties [11]. Its interference with both estrogen receptors (ER␣) and (ER␤) has been studied in detail [12][13][14].…”

Differential estrogen receptor subtype modulators: Assessment of estrogen receptor subtype-binding selectivity and transcription-regulating properties of new cycloalkyl pyrazoles

“…The X-ray structures of the ligand-binding domains of ER␣ and ER␤ with 17␤-estradiol (estradiol), raloxifene, 4-hydroxy-tamoxifen, diethylstilbestrol or genistein, revealed the molecular determinants of ER subtypespecific ligand binding and regulation of transcription ( [1,2] and references therein). While the affinity of ligand binding to either form of ER primarily reflects the presence of two hydroxyl groups with an O-O distance close to that between the 3-and 17␤-hydroxyl groups of estradiol, the ability of raloxifene and 4-hydroxy-tamoxifen to display tissue-specific ER antagonist activity depends on their lengthy side chains, which can stabilize receptor conformations capable of recruiting transcriptional co-repressors rather than co-activators depending on the relative levels of expression of these co-regulators in a particular cell or tissue [1,2,4]. Ligands lacking lengthy extensions but possessing core features (e.g.…”