Evaluation of the binding efficacy of flavonol derivatives on estrogen receptors (ER) with respect to ring B hydroxylation

• Published in: Results in Chemistry 2024-01, Vol.7, p.101544, Article 101544
• Main Authors: Safna Hussan, K.P, Davis, Anu, Lekshmi, S., Shahin Thayyil, Mohamed, Chathrattil Raghavamenon, Achuthan, Devassy Babu, Thekkekara
• Format: Article
• Language: English
• Subjects: Density Functional Theory; Estrogen Receptors; Flavonol derivative; Molecular Docking
• ISSN: 2211-7156; 2211-7156
• DOI: 10.1016/j.rechem.2024.101544

[Display omitted] Flavonols are a class of flavonoids, consist of two aromatic rings (A and B) connected by a three-carbon bridge, forming a closed pyran ring (C) with a hydroxyl group at position 3. Galangin is a form of flavonols formed with additional hydroxyl groups at ring A positions 5 and 7. The hydroxylation at ring B of galangin may result in resonance and delocalization of electrons and the formation of different derivatives like kaempferol, quercetin, and myricetin. Most of these flavonols have a similarity to 17β-estradiol, the steroid sex hormone which bound to estrogen receptors (ER), a class of nuclear transcription factors involved in the regulation of many complex pathophysiological processes including breast cancer genesis and progression. Various studies have reported that most of the flavonols are antiestrogenic and show anticancer potential, but the mechanisms may be varied like estrogenic, anti-estrogenic, non-estrogenic, and biphasic activities and their mechanisms of action have not been systematically evaluated. The goal of this study is to ascertain the possible interactions of flavonol derivatives to ER with respect to ring B hydroxylation and the unsaturation degree of the C2′=C3′ bond. The variations in structure, frontier molecular orbital, molecular electrostatic potential maps, Mullikan charge population of derivatives was determined by Density functional theory (DFT) calculations at B3LYP/6-311G (d,p) level on model molecular systems. A deep insight into these interactions with ER was described by molecular docking studies. Results shows that the flavonol was found more affinity to ERβ and the efficacy was increased with respect to the OH group on ring B. The hydroxyl group at position 3 and 5 in ring A and C are not found much relevant. The site of ERβ is more hydrophilic while binding ligand and the electropositive and electronegative area of the molecule was increased and reaches a maximum for quercetin with the 3 OH group; after that, it found to diminish. Moreover, the reduced cavity size of ERβ and the replacement of LEU384 with polar HIE475 and MET336 increased the polarity and hydrophilicity of the cavity and led to more electrostatic interaction with ligands. ERα is found to be hydrophobic and the polar interaction between the ligands and ERα is less due to open confirmation of the cavity and bulk empty space. The results also emphasize that myricetin and quercetin require less energy to activate while accounting f