title: Human ketosteroid receptors interact with hazardous phthalate plasticizers and their metabolites: an in silico study.
abstract: 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.
authors: Enzyme Technology Laboratory, Biotechnology Division, Department of Botany, University of Calicut, Kerala, India.|Research and Post Graduate Department of Chemistry, Sri Vyasa N.S.S. College, Wadakkanchery, Thrissur, University of Calicut, Kerala, India.
authors: M K
authors: MK
authors: Sarath Josh
authors: Enzyme Technology Laboratory, Biotechnology Division, Department of Botany, University of Calicut, Kerala, India.
authors: S
authors: S
authors: Pradeep
authors: Research and Post Graduate Department of Chemistry, Sri Vyasa N.S.S. College, Wadakkanchery, Thrissur, University of Calicut, Kerala, India.
authors: K S
authors: KS
authors: Vijayalekshmy Amma
authors: Department of Chemistry, Mahatma Gandhi College, Thiruvananthapuram, University of Kerala, Kerala, India.
authors: R
authors: R
authors: Sudha Devi
authors: Department of Chemistry, Mahatma Gandhi College, Thiruvananthapuram, University of Kerala, Kerala, India.
authors: S
authors: S
authors: Balachandran
authors: Centre for Cheminformatics, Department of Chemistry, Malabar Christian College, Kozhikode, University of Calicut, Kerala, India.
authors: M N
authors: MN
authors: Sreejith
authors: Enzyme Technology Laboratory, Biotechnology Division, Department of Botany, University of Calicut, Kerala, India.
authors: Sailas
authors: S
authors: Benjamin
mesh_terms: D001665:Binding Sites; D001711:Biotransformation; D019295:Computational Biology / Q000379:methods; D030562:Databases, Protein; D052244:Endocrine Disruptors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004785:Environmental Pollutants / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D005103:Expert Systems; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010795:Phthalic Acids / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D012984:Software; D066007:Toxicokinetics
chemical_list: C410798:AR protein, human; D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D008024:Ligands; C497713:NR3C1 protein, human; D010446:Peptide Fragments; D010795:Phthalic Acids; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone
keywords: endocrine disruptor; in silico; ketosteroid receptors; molecular docking; phthalates