In silico evidences for the binding of phthalates onto human estrogen receptor α, β subtypes and human estrogen-related receptor γ

Being lipophilic xenobiotic chemicals, phthalates from the surrounding environments can easily be absorbed into the biological system, thereby causing various health problems including cancer and endocrine disruption in test animals and also in humans. In the present in silico study employing Glide, Schrodinger Suite 2012, we analysed in detail the binding affinities of 12 commonly used diphthalates and their metabolites (corresponding mono ester and phthalic acid) onto the ligand-binding domain (LBD) of the human estrogen receptor (hER), human estrogen receptor (hER) and human estrogen related receptor (hERR). Natural ligand 17 estradiol (E2), known xenoestrogen bisphenol A, the phytoestrogen genistein, the agonists/antagonists 4-hydroxy tamoxifen and raloxifene were also docked onto these receptors as positive controls for comparing the binding efficiencies with that of phthalates and their metabolites. Results revealed that E2 had less binding affinity to the receptors in comparison to certain phthalates, i.e. maximum binding scores (G score, kcal/mol) were diisononyl phthalate (-9.44) to hER, monophenyl phthalate (-8.66) to hER and di(2-ethylhexyl)phthalate (-9.38) to hERR. The most concerned monophthalates established additional H bonds with certain surrounding crucial amino acid residues in the LBD, and thus showed more affinity to all the receptors than even the natural ligand and other well-characterised xenoestrogens as demonstrated in this study. Briefly, this study gives an insight into the virtual binding behaviours of commonly used phthalates and their metabolites onto hERs and hERR, which would accelerate further in vitro mechanistic, preclinical and clinical studies on real in vitro or in vivo platforms.