Possible molecular interactions of naringin with the estrogen receptor and the aryl hydrocarbon receptor studied in silico

Abstract

Cells constantly adapt and respond to molecular changes in their microenvironment. The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR), is sensitive to endogenous (oxygen tension, redox potential) and exogenous (polyaromatic hydrocarbons -aryls- and environmental toxins) factors. Activated AHR translocates to the nucleus and remains inactive in the cytosol complexed with other proteins (HSP90, AIP or XAP2, p23 and SRC). The AHR complex and its translocator protein interact with the estrogen receptor (ESR). Estradiol represses AHR in granulosa and ovarian tissue. AHR causes degradation of ESR by proteasome. Activation of AHR by cigarette smoke targets pathogenic TH17 cells to autoimmunity and activates mast cells and macrophages in allergies. Naringin (NGN) is an antitumor flavonoid that inhibits aromatase activity. In silico studies place NGN in the ligand niche in ESR. But NGN is 1000 times more soluble than estradiol, which represents a thermodynamic barrier. We investigated the interaction of ESR and AHR with NGN in silico.

We employed 1GWR, 7ZUB structures (RSCB PDB), respectively that were edited to perform blind binding assays (without posing the ligand in the ligand domain) with implicit solvent and molecular dynamics in explicit solvent with widely used free software (OpenChimera, AutoDock, EADock, CharMM forcefields, NAMD). NGN conformations were obtained from ZINC and PubChem and minimized prior to testing.

We found that the minimum binding delta Gs are similar (ESR -8.32 ± 0.34 and AHR -7.56 ± 0.41 Kcal/mol+- sigma) with NGN outside the ligand niche. The Van der Waals volume of NGN would correspond to that of the interactions of  ESR-Corepressor and AHR-AIP.

These observations are contrary to what is reported in the literature, but coincide with structures of NGN bound to MIF observed by RX diffraction (RSCB PDB). It remains to be determined whether NGN competes with ESR Corepressor and AIP for their respective binding sites and whether NGN-XR complexes have different affinity for natural ligands to construct any rigorous mechanistic hypothesis, which requires greater computational power.