Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

Abstract

Flavonoids are plant bioactives that are recognized as hormone-like polyphenols because of their similarity to the endogenous sex steroids 17β-estradiol and testosterone, and to their estrogen- and androgen-like activity. Most efforts to verify flavonoid binding to nuclear receptors (NRs) and explain their action have been focused on ERα, while less attention has been paid to other nuclear and non-nuclear membrane androgen and estrogen receptors. Here, we investigate six flavonoids (apigenin, genistein, luteolin, naringenin, quercetin, and resveratrol) that are widely present in fruits and vegetables, and often used as replacement therapy in menopause. We performed comparative computational docking simulations to predict their capability of binding nuclear receptors ERα, ERβ, ERRβ, ERRγ, androgen receptor (AR), and its variant ART877A and membrane receptors for androgens, i.e., ZIP9, GPRC6A, OXER1, TRPM8, and estrogens, i.e., G Protein-Coupled Estrogen Receptor (GPER). In agreement with data reported in literature, our results suggest that these flavonoids show a relevant degree of complementarity with both estrogen and androgen NR binding sites, likely triggering genomic-mediated effects. It is noteworthy that reliable protein–ligand complexes and estimated interaction energies were also obtained for some suggested estrogen and androgen membrane receptors, indicating that flavonoids could also exert non-genomic actions. Further investigations are needed to clarify flavonoid multiple genomic and non-genomic effects. Caution in their administration could be necessary, until the safe assumption of these natural molecules that are largely present in food is assured.

Endocrine Disruptors and Prostate Cancer

“…Four distinct proteins (TRPM8, OXER1, ZIP9 and GPRC6A) localized at the plasma membrane of prostate epithelial cells have been proposed as mARs [13]. TRPM8, OXER1, and GPRC6A activities are also modulated by endogenous ligands structurally unrelated to androgens, whereas ZIP9 appears to be activated solely by androgens [14,57].…”

“…TRPM8, a member of the melastatin-related transient receptor potential family, is a Ca 2+ -selective cation androgen-regulated channel. TRPM8 is expressed throughout the male urogenital tract and in other different tissues such as the peripheral nervous system [13,14,[58][59][60][61]. The role of TRPM8 in PCa appeared to occur in early-stage prostate tumors, in which it is significantly up-regulated [13,14,59,62], whereas its expression is reduced in androgen-independent advanced stages of PCa, and it has no effect on cell migration, proliferation, and invasion [14,56,63].…”

“…TRPM8 is expressed throughout the male urogenital tract and in other different tissues such as the peripheral nervous system [13,14,[58][59][60][61]. The role of TRPM8 in PCa appeared to occur in early-stage prostate tumors, in which it is significantly up-regulated [13,14,59,62], whereas its expression is reduced in androgen-independent advanced stages of PCa, and it has no effect on cell migration, proliferation, and invasion [14,56,63]. TRPM8 has been recognized as an AR because of its steroid specificity and androgen-binding affinity [13].…”

“…This includes the transient receptor potential melastatin 8 (TRPM8), the oxoeicosanoid receptor 1 (OXER1), the zinc transporter ZIP9/SLC39A (namely, Zrt-and Irt-like Protein 9 or Solute Carrier family 39 member 9), and the G-protein-coupled receptor family C group 6 member A (GPRC6A). These proteins have been proposed as alternative membrane androgen receptors (mARs) that could be involved in the survival of PCa cells [13,14].…”

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

“…For OXER1, different antagonists were synthetized and screened both in vitro and in vivo, mostly for their ability to reduce inflammation-related pathways. In addition, several natural compounds were examined for their binding affinity for ZIP9, OXER1 and GPRC6A, although this analysis was limited to in silico data [ 227 ]. For mPRα and PGRMC1, an agonist and antagonist compounds have been reported, respectively.…”