Abstract
Most estrogen receptor α (ERα) ligands target the ligand binding domain (LBD). Agonist 17β-estradiol (E2) and tamoxifen (TM, known SERM), bind to the same site within the LBD. However, structures of ligand-bound complexes show that E2 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-E2 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.
Highlights
Estrogens cohere with the estrogen receptors (ERs) and employ their physiological effects
We presumed that the ligand which will bind to 3ERT effectively might behave as an antagonist whereas which will interact significantly with 1GWR may function as an agonist
We found that most of the flavonoids selected for the studies bind to both 3ERT and 1GWR
Summary
Estrogens cohere with the estrogen receptors (ERs) and employ their physiological effects. They are the members of the nuclear receptor (NR) superfamily[1,2] of the ligand-activated transcription factors. The H12 of LBD adopts discrete ligand-dependent conformation, accountable for the receptor activation and plays the crucial molecular switch (Fig. 1b,c)[12,13]. The interaction of LBD with an antiestrogenic inhibits receptor activation[14] because H12 migrates from its natural position and causes the distortion of co-regulator binding indentation. Phytoestrogens, are a group of naturally occurring compounds present in plants. They have the ability to bind to the ERs and to stimulate estrogen-dependent transcription[15]. Phytoestrogens are only weakly estrogenic; their activity is 1/100 times lower than that of E216
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