title: Molecular interactions of dioxins and DLCs with the ketosteroid receptors: an in silico risk assessment approach.
abstract: Dioxins and dioxin-like compounds (DLCs) are the ones with poor water solubility and low volatility, resistant to physical, chemical and biological processes, persistent in the environment even under extreme conditions. Due to lipophilic nature, they get adhered to the fatty material and concentrate through biomagnification and bioaccumulation, thereby easily getting incorporated into food chains, paving the way to endocrine disruption via modulation of various human receptors. This in turn leads to certain adverse health effects. In the present study, a total of 100 dioxins and DLCs were taken and their binding pattern was assessed with the ketosteroid receptors, i.e. androgen (hAR), glucocorticoid (hGR), progesterone (hPR) and mineralocorticoid (hMR) in comparison to the corresponding natural steroids and a known endocrine disrupting xenobiotic, Bisphenol A (BPA). Most of the DLCs, particularly those bearing hydroxyl (-OH) group showed considerable affinities with ketosteroid receptors. On comparing D scores of all the dioxins and DLCs against all four receptors, compound 8-hydroxy-3,4-dichlorodibenzofuran(8-OH-DCDF) exhibited least D score of -9.549 kcal mol-1against hAR. 3,8-Dihydroxy-2-chlorodibenzofuran(3,8-DiOH-CDF), 4'-hydroxy-2,3,4,5-tetrachlorobiphenyl (4'-OH-TCB) and 4-hydroxy-2,2',5'-trichlorobiphenyl(4-OH-TCB) also showed comparable molecular interactions with the ketosteroid receptors. These interactions mainly include H-bonding, π-π stacking, hydrophobic, polar and van der Waals' interactions. In contrast, BPA and some natural ligands tested in this study showed lower binding affinities with these receptors than certain DLCs reported herein, i.e. certain DLCs might be more toxic than the proven toxic agent, BPA. Such studies play a pivotal role in the risk assessment of exposure to dioxins and DLCs on human health.
authors.affiliation: a Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Jamia Hamdard , New Delhi , India.
authors.forename: Mohemmed Faraz
authors.initials: MF
authors.lastname: Khan
authors.affiliation: a Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Jamia Hamdard , New Delhi , India.
authors.forename: Mohammad Mumtaz
authors.initials: MM
authors.lastname: Alam
authors.affiliation: a Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Jamia Hamdard , New Delhi , India.
authors.forename: Garima
authors.initials: G
authors.lastname: Verma
authors.affiliation: a Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Jamia Hamdard , New Delhi , India.
authors.forename: Wasim
authors.initials: W
authors.lastname: Akhtar
authors.affiliation: b Department of Biosciences , Jamia Millia Islamia , New Delhi , India.
authors.forename: Moshahid Alam
authors.initials: MA
authors.lastname: Rizvi
authors.affiliation: c CSIR-Indian Institute of Integrative Medicine , Jammu , India.
authors.forename: Asif
authors.initials: A
authors.lastname: Ali
authors.affiliation: a Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Jamia Hamdard , New Delhi , India.
authors.forename: Mymoona
authors.initials: M
authors.lastname: Akhter
authors.affiliation: a Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Jamia Hamdard , New Delhi , India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shaquiquzzaman
mesh_terms: D004147:Dioxins / Q000737:chemistry*; D052244:Endocrine Disruptors / Q000737:chemistry*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007664:Ketosteroids / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011987:Receptors, Steroid / Q000737:chemistry*; D015203:Reproducibility of Results; D018570:Risk Assessment
chemical_list: D004147:Dioxins; D052244:Endocrine Disruptors; D007664:Ketosteroids; D008024:Ligands; D011987:Receptors, Steroid
keywords: Molecular docking; dioxins; endocrine disruptors; ketosteroid receptors; risk assessment