Determination and analysis of agonist and antagonist potential of naturally occurring flavonoids for estrogen receptor (ERα) by various parameters and molecular modelling approach

Abstract

Most estrogen receptor α (ERα) ligands target the ligand binding domain (LBD). Agonist 17β-estradiol (E 2 ) and tamoxifen (TM, known SERM), bind to the same site within the LBD. However, structures of ligand-bound complexes show that E 2 and TM induce different conformations of helix 12 (H12). During the molecular modelling studies of some naturally occurring flavonoids such as quercetin, luteolin, myricetin, kaempferol, naringin, hesperidin, galangin, baicalein and epicatechin with human ERα (3ERT and 1GWR), we observed that most of the ligands bound to the active site pocket of both 3ERT and 1GWR. The docking scores, interaction analyses, and conformation of H12 provided the data to support for the estrogenic or antiestrogenic potential of these flavonoids to a limited degree. Explicit molecular dynamics for 50 ns was performed to identify the stability and compatibility pattern of protein-ligand complex and RMSD were obtained. Baicalein, epicatechin, and kaempferol with 1GWR complex showed similar RMSD trend with minor deviations in the protein backbone RMSD against 1GWR-E 2 complex that provided clear indications that ligands were stable throughout the explicit molecular simulations in the protein and outcome of naringin-3ERT complex had an upward trend but stable throughout the simulations and all molecular dynamics showed stability with less than overall 1 Å deviation throughout the simulations. To examine their estrogenic or antiestrogenic potential, we studied the effect of the flavonoids on viability, progesterone receptor expression and 3xERE/3XERRE-driven reporter gene expression in ERα positive and estrogen responsive MCF-7 breast cancer cells. Epicatechin, myricetin, and kaempferol showed estrogenic potential at 5 µM concentration.

Computational Approaches for the Discovery of GPER Targeting Compounds

“…Molecular docking on GPER structures extracted from all-atom MD has demonstrated ( 48 ) that the natural polyphenol (–)-epicatechin (see Figure 2 ) has the ability to anchor to this receptor with a binding mode similar to the agonist G-1. It is interesting to note that flavonoids sharing structural similarities to estrogens, such as genistein and other phytoestrogens ( 49 – 51 ), not only bind but also activate the classical receptors ERα and ERβ. In contrast, and in spite of its evident structural analogies to these phytochemicals, (–)-epicatechin fails to bind ERα and ERβ.…”

Association between Polyphenol Intake and Breast Cancer Risk by Menopausal and Hormone Receptor Status

“…This protective associations could be explained by the ability of some polyphenol subclasses to generate similar responses to estrogen (phytoestrogens), as their structure resembles the most important type of estrogen in humans and possesses hydroxyl groups and phenolic rings, necessary for binding to estrogen receptors [46]. In addition, several studies reported that some of the estrogen receptor (ER)-mediated responses induced by flavonoids are comparable, or even superior, to those induced by physiological levels of estradiol [47].…”

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

“…Indeed, the same signaling pathways are regulated by CYP450–estradiol interactions, and there are plenty of data available on this topic. Moreover, other calculation methods are also applied, including ADMET and molecular dynamics (MD) [ 90 , 91 ] (for MD description and examples, see Section 2.1.3 ). Nowadays, in silico methods are a standard tool in plant xenoestrogens studies.…”