Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor [alpha], [beta], [gamma] subtypes: an in silico approach

• Published in: Journal of applied toxicology 2014-07, Vol.34 (7), p.754-765
• Main Authors: Sarath Josh, MK, Pradeep, S, Vijayalekshmi Amma, KS, Balachandran, S, Abdul Jaleel, UC, Doble, Mukesh, Spener, Friedrich, Benjamin, Sailas
• Format: Article
• Language: English
• Subjects: Affinity; Binding; Bisphenol A; Drugs; Ligands; Metabolites; Phthalates; Plastics; Receptors; Surgical implants; Toxicology
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.2902

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) [alpha], [beta] and [gamma] 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, Schrodinger 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 ([gamma]), 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 hPPAR[beta]. Hazardous di(2-ethylhexyl)phthalate generally showed a greater preference to hRXRs than hPPARs, but its highest G score (-10.87) was with hRXR[alpha]; 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 hRXR[beta]. 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. Copyright copyright 2013 John Wiley & Sons, Ltd. This exhaustive in silico study looks into the molecular interactions of 15 hazardous diphthalates, their metabolites vis-a-vis certain natural and synthetic ligands with nuclear hPPAR and hRXR receptor subtypes via molecular docking using Glide. DIDP showed highest G score with hPPAR[gamma], while DEHP generally showed a greater preference to hRXRs than hPPARs and showed highest G score with hRXR[alpha]. These in silico evidences would lead to further in vitro mechanistic as well as in vivo preclinical and clinical studies.