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  • The intimate interactions between flavonoids and ER have bee

    2019-12-16

    The intimate interactions between flavonoids and ERα have been more extensively studied than their ERβ interactions because of the dominant role of ERα in some important diseases (Ye et al., 2018) including breast cancer (more than 80% of human breast cancers are ERα positive) (Turner et al., 2015), atherosclerosis (Evangelopoulos et al., 2003), ovarian cancer (Lu et al., 2006), and ERα′s potential role in diabetes because of its role in regulation of glucose homeostasis (Bryzgalova et al., 2006). Since there is more structural information (e.g. X-ray crystallography) (Brzozowski et al., 1997); for ERα than ERβ, we are able to construct a good ERα in silico model – for this reason we have focused our food in silico functionality molecular mechanism studies on ERα/food flavonoid interactions. In the context of receptor (e.g., ERα)-mediated biological activity, the structure-affinity relationship is the interdependency between ligand structures and receptor binding affinity (i.e. ligand/receptor fit) (Ye et al., 2018). Structure-affinity relationships are good predictors of biological activity (including toxicity) and are useful screening methods to select potential new receptor-mediated TCS JNK 5a australia for pharmaceutical development (Hall et al., 2003). This has led to in silico studies becoming a key tool in drug discovery and development (Ekins et al., 2007) - our studies extend this thinking to food functionality. Flavonoids are important food components that impart significant biological activity including estrogenicity, which is a key factor in food functionality (e.g., isoflavone-rich bread is used as partial ‘hormone’ replacements in peri- and postmenopausal women (Simons et al., 2000)). Further to this, Zhang et al. (2018) studied both ERα interactions in silico and biological effects in a cultured cell system of coumarins and meroterpenes from Cullen corylifolium (a plant used in Chinese herbal medicine). They showed that the 6 compounds studied (psoralen, angelicin, trioxsalen, psorilidin and bakuchiol) interacted with the ERα LBC in silico studies and were estrogenic in luciferase-based ERα cell assays. They concluded that a better fit to the ERα LBC and a greater estrogenicity was associated with longer molecules with hydroxyl groups that could interact with the LBC by forming hydrogen bonds. In this paper, we report the structure-affinity relationship between ERα and flavonoid ligands in silico (using the Schrödinger platform). We use these findings to better understand flavonoid estrogenicity and, importantly, the estrogenicity changes that might result following flavonoid metabolism (e.g., by the gut microbiome); we discuss our findings in the context of food functionality and toxicity.
    Experimental
    Results and discussion
    Conclusions This study shows, firstly, that both the number of phenolic hydroxyls on a ligand molecule and their relative positions and special arrangements can affect the hydrogen bond interaction between the ligand and key amino acid residues in the ERα′s LBC. In addition, different flavonoid electron donors (e.g., methoxy or hydroxy) likely result in different hydrogen bond energies. This, in turn, might result in different binding energies which would likely influence estrogenicity. For example, genistein has 5-, 7- and 4′-hydroxyl groups, whereas biochanin A has 5- and 7-hydroxyl groups with a methoxy group at the 4′ position (Table 2). This might explain the estrogenicity differences between these two compounds (Table 2). The balance between dietary phytoestrogen and endogenous estrogen levels should be considered; for example, isoflavone supplements are sometimes used to alleviate symptoms of menopause (Potter et al., 1998) because they enhance total plasma estrogenicity, thus ameliorating the biochemical and physiological effects of declining natural estrogens. On the other hand, TCS JNK 5a australia women with high circulating estrogen levels (e.g., child-bearing age women) would be unlikely to benefit from isoflavone dietary supplementation. A similar argument applies to the implications of dietary phytoestrogen to breast cancer risk where high isoflavone (e.g., genistein) doses appear to prevent breast cancer cell proliferation, whereas low doses promote proliferation (He and Chen, 2013). And, importantly, dietary phytoestrogens can interfere with the action of estrogen receptor-based (e.g., tamoxifen) treatment for breast cancer because they might compete with tamoxifen for occupancy of the LBC, even though the phytoestrogens have a very much lower binding affinity for the LBC than tamoxifen (Ju et al., 2002).