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

Abstract

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.

Insights into the molecular properties underlying antibacterial activity of prenylated (iso)flavonoids against MRSA

“…Prenylated isoflavonoids (glabrene, 3′-hydroxy-4′- O -methyl-glabridin, 4′- O -methyl-glabridin, hispaglabridin A, hispaglabridin B, glyceofuran, glyceollidin II, glyceollin I, glyceollin II, glyceollin III, glyceollin IV, glyceollin V, dehydroglyceollidin II, dehydroglyceollin I, dehydroglyceollin II, dehydroglyceollin, III, dehydroglyceollin IV) and one prenylated flavone (glabrol) were previously purified and chemically characterized 22 , 23 . Wighteone, lupiwighteone, luteone, 2,3-dehydrokievitone, licoisoflavone A, neobavaisoflavone, iso-osajin and 6,8-diprenygenistein were purchased from Plantech UK (Reading, UK).…”

QSAR-based molecular signatures of prenylated (iso)flavonoids underlying antimicrobial potency against and membrane-disruption in Gram positive and Gram negative bacteria

“…Prenylated isoflavonoids (glabrene, 3′-hydroxy-4′- O -methyl-glabridin, 4′- O -methyl-glabridin, hispaglabridin A, hispaglabridin B, glyceofuran, glyceollidin II, glyceollin I, glyceollin II, glyceollin III, glyceollin IV, glyceollin V, dehydroglyceollidin II, dehydroglyceollin I, dehydroglyceollin II, dehydroglyceollin, III, dehydroglyceollin IV) and one prenylated flavone (glabrol) were previously purified and chemically characterized 45 , 46 . 6-Prenylnaringenin, propidium iodine (PI), Phe-Arg β-naphthylamide dihydrochloride (PaβN), ampicillin and ciprofloxacin were purchased from Sigma Aldrich (St. Louis, MO, USA).…”

The Potent Phytoestrogen 8-Prenylnaringenin: A Friend or a Foe?

“…Moreover, no evidence was found for any estrogen antagonist action by 8-PN at concentrations of up to 10 −6 M [ 62 ]. Likewise, results from a yeast-based estrogen bioassay indicated a purely agonistic action at both ER subtypes [ 69 ]. In silico modeling of ER binding further suggested that chain prenylation without an increase in molecular length, which enables 8-PN to fit into the hydrophobic pocket in the human ER, is responsible for the high agonist activity of 8-PN compared with naringenin [ 69 ].…”