title: Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor α, β, γ subtypes: an in silico approach.
abstract: 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, β 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 hPPARβ. 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 hRXRβ. 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.
authors.affiliation: Enzyme Technology Laboratory, Biotechnology Division, Department of Botany, University of Calicut, Kozhikode, Kerala, 673 635, India; Department of Chemistry, Sri Vyasa N.S.S. College, Wadakkanchery, University of Calicut, Thrissur, Kerala, 680 582, India.
authors.forename: M K
authors.initials: MK
authors.lastname: Sarath Josh
authors.forename: S
authors.initials: S
authors.lastname: Pradeep
authors.forename: K S
authors.initials: KS
authors.lastname: Vijayalekshmi Amma
authors.forename: S
authors.initials: S
authors.lastname: Balachandran
authors.forename: U C
authors.initials: UC
authors.lastname: Abdul Jaleel
authors.forename: Mukesh
authors.initials: M
authors.lastname: Doble
authors.forename: Friedrich
authors.initials: F
authors.lastname: Spener
authors.forename: Sailas
authors.initials: S
authors.lastname: Benjamin
mesh_terms: D001559:Benzhydryl Compounds / Q000378:metabolism; D006801:Humans; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D010636:Phenols / Q000378:metabolism; D010795:Phthalic Acids / Q000378:metabolism*; D000077205:Pioglitazone; D010968:Plasticizers / Q000378:metabolism; D011487:Protein Conformation; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D049230:Retinoid X Receptor beta / Q000378:metabolism*; D047491:Retinoid X Receptor gamma / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D047492:Peroxisome Proliferator-Activated Receptors; D010636:Phenols; D010795:Phthalic Acids; D000077205:Pioglitazone; D010968:Plasticizers; D047490:Retinoid X Receptor alpha; D049230:Retinoid X Receptor beta; D047491:Retinoid X Receptor gamma; D000077154:Rosiglitazone; D045162:Thiazolidinediones; C032279:phthalic acid; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: In silico; bisphenol A; endocrine disruptor; hPPARs; hRXRs; molecular docking; phthalate