Accessing the molecular interactions of phthalates and their primary metabolites with the human pregnane X receptor using in silico profiling.

Phthalates are known to cause endocrine disruption in humans and animals. Being lipophilic xenobiotic chemicals, phthalates from the surrounding environments can easily be absorbed into the biological system, thereby causing various health dysfunctions. This molecular docking study evaluates a variety of molecular interactions of 12 commonly used diphthalates and respective monophthalates onto the ligand binding domain (LBD) of the human pregnane X receptor (hPXR), a xenosensor, which would be beneficial for further in vitro and in vivo studies on hazardous phthalates. Out of 12 diphthalates and their monophthalates tested, diisodecyl phthalate (-9.16 kcal mol-1 ) showed more affinity toward hPXR whereas diisononyl phthalate (-8.77) and di(2-ethyhexyl)phthalate (-8.56), the predominant plasticizers found in a variety of plastics and allied products, showed comparable binding scores with that of the control ligands such as hyperforine (-9.99) and dexamethasone (-7.36). In addition to the above diphthalates, some of their monophthalates (monoisodecyl phthalate, mono-2-etheylhexyl phthalate, etc.) also established similar interactions with certain crucial amino acids in the LBD, which led to higher G scores. In fact, bisphenol A, a well-studied and proven endocrine disruptor, showed lesser G scores (-6.69) than certain phthalates. Copyright © 2016 John Wiley & Sons, Ltd.

Human ketosteroid receptors interact with hazardous phthalate plasticizers and their metabolites: an in silico study.

Phthalic acid esters or phthalates are ubiquitous environmental pollutants known for their adverse health effects in test animals and, of late, in humans. Thus, in this molecular docking study - using Glide (Schrödinger) - the molecular interactions of 31 ligands, including 12 diphthalates, their monophthalates and phthalic acid with selected human ketosteroid receptors, i.e., androgen (hAR), progesterone (hPR) and glucocorticoid (hGR) receptors were explored and their binding affinities were compared with that of corresponding natural steroids and a known endocrine disrupting xenobiotic, bisphenol A (BPA). Mostly, diphthalates and monophthalates showed the potential for antisteroidal activity by interacting with hAR, hPR and hGR. Of them, diphenyl phthalate showed the highest G score (-7.70 kcal mol(-1) ) with hAR, and the crucial amino acid (aa) residues in the ligand binding domain (LBD) of this receptor involved in the molecular interactions were Phe 764, Leu 704, Asn 705 and Thr 877. The mono-iso-decyl phthalate showed the highest G score (-8.36) with the hPR, and the crucial aa residues in the LBD interactions were Arg 766 Gln 725 and Phe 778. The mono-iso-decyl phthalate also showed more affinity (-8.44) towards hGR than the natural ligand, and the aa residues in the LBD interactions were Gln 570 and Met 604. In addition to these, some other phthalates established comparable interactions with certain aa residues located in the LBD of these receptors, which resulted in higher G scores. Contrastingly, BPA and some natural ligands tested in this study showed lower G scores with these receptors than certain phthalates reported herein, i.e., certain phthalates are more toxic than the proven toxic BPA. Copyright © 2015 John Wiley & Sons, Ltd.

Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor α, ß, γ subtypes: an in silico approach.

This exhaustive in silico study looks into the molecular interactions of phthalates and their metabolites with human peroxisome proliferator-activated receptor (hPPAR) and retinoid X receptor (hRXR) α, ß and γ subtypes--the nuclear receptor proteins function as transcription factors by regulating the expression of downstream genes. Apart from the much discussed plasticizer bisphenol A, we examined the binding affinities of 15 common diphthalates and their monophthalates, natural (linoleic acid, conjugated linoleic acid) and synthetic (bezafibrate, pioglitazone, GW 50156) ligands with hPPARs. In addition to these phthalates, specific natural (retinoic and phytanic acids) and synthetic (bexarotene, rosiglitazone) ligands were examined with hRXRs. The Maestro, Schrödinger Suite 2012 was used for the molecular docking study. In general, natural ligands of hPPAR showed less binding efficiencies than phthalic acid esters and drugs. The diphthalate di-iso-decyl phthalate showed the highest G score (-9.99) with hPPAR (γ), while its monophthalate (mono-iso-decyl phthalate) showed a comparatively less G score (-9.56). Though the PPAR modulator GW 50156 showed strong affinity with all hPPAR subtypes, its highest G score (-12.43) was with hPPARß. Hazardous di(2-ethylhexyl)phthalate generally showed a greater preference to hRXRs than hPPARs, but its highest G score (-10.87) was with hRXRα; while its monophthalate (Mono(2-ethylhexyl)phthalate) showed a lesser G score (-8.59). The drug bexarotene showed the highest G score (-13.32) with hRXRß. Moreover, bisphenol A showed more affinity towards hRXR. Briefly, this study gives an overview on the preference of phthalic acid esters, natural and synthetic ligands on to hPPAR and hRXR subtypes, which would lead to further in vitro mechanistic as well as in vivo preclinical and clinical studies.

Achromobacter denitrificans SP1 produces pharmaceutically active 25C prodigiosin upon utilizing hazardous di(2-ethylhexyl)phthalate.

This first report describes the purification and identification of an orange-red pigment produced by Achromobacter denitrificans strain SP1 (isolated from sewage sludge heavily contaminated with plastics) during its growth in a simple basal salt medium supplemented with the hazardous di(2-ethylhexyl)phthalate (DEHP) blended in PVC blood bag (in situ) or free DEHP (ex situ) as carbon source. The cell-bound pigment was elucidated, characterized at molecular level, and described as an unusual 25C prodigiosin analog for the first time. At laboratory conditions (in flasks), the dry cell mass was 75.2mg/g blood bag, which upon extraction yielded 7.1mg prodigiosin; at this stage the pH of the medium was dropped from 7.2 to 3.5. Considering its pharmaceutical importance, taking 10 known prodigiosins as controls, this 25C prodigiosin was subjected to molecular docking studies, showed comparable and promising binding efficiencies with the crucial molecular human targets like cycloxygenase-2, ZAP-70 kinase and Jak-3 kinase.