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

• Published in: Journal of applied toxicology 2016-12, Vol.36 (12), p.1599-1604
• Main Authors: Sarath Josh, M. K., Pradeep, S., Balan, Aparna K., Sreejith, M. N., Benjamin, Sailas
• Format: Article
• Language: English
• Subjects: Binding Sites; bisphenol A; Computational Biology; endocrine disrupting compounds; Endocrine Disruptors - chemistry; Endocrine Disruptors - metabolism; Endocrine Disruptors - toxicity; Glide; human pregnane X receptor; Humans; in silico profiling; Ligands; Molecular Docking Simulation; phthalates; Phthalic Acids - chemistry; Phthalic Acids - metabolism; Phthalic Acids - toxicity; Protein Binding; Receptors, Steroid - metabolism; Structure-Activity Relationship
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.3321

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. This molecular docking study using Glide evaluates a variety of molecular interactions of 12 commonly used diphthalates (generally reported as hazardous) and respective monophthalates with the ligand binding domain of the human pregnane X receptor (hPXR). Diisodecyl phthalate showed more affinity towards hPXR; whereas diisononyl phthalate and di(2‐ethyhexyl)phthalate, the predominant plasticizers found in a variety of plastics and allied products, showed moderate binding. A higher affinity of certain phthalates to hPXR than its natural ligands and BPA (a proven endocrine disruptor) is alarming.