Ahmad Shahzad, Khan Mohemmed Faraz, Parvez Suhel, Akhtar Mohammad, Raisuddin Sheikh
Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi, 110062, India.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, 110062, India.
J Appl Toxicol. 2017 Mar;37(3):265-277. doi: 10.1002/jat.3355. Epub 2016 Jul 18.
Glucocorticoids (GCs) are well known to exert broad-based effects on metabolism, behavior and immunity. Their impaired synthesis and production lead to adverse health effects. Some environmental toxicants, including phthalate esters (PAEs), are associated with endocrine disruption. These endocrine-disrupting chemicals (EDCs) also cause adrenal toxicity and alteration of GC biosynthesis and their functions. Using in silico tools of Schrodinger Maestro 9.4, we performed a molecular docking study of 32 ligands including PAEs of a known endocrine-disrupting potential with the selected enzymes of the GC biosynthesis pathway (GBP) such as CYP11A1, CYP11B2, CYP19A1, CYP17A1, CYP21A2 and 3α/20β-HSD. Binding affinities of the PAEs were compared with known inhibitors of these enzymes. Amongst PAEs, diphenyl benzene-1, 2 - dicarboxylate (DPhP) showed the lowest docking score of -8.95616 kcal mol against CYP21A1. Besides, benzyl butyl benzene-1,2-dicarboxylate (BBzP), bis(7-methylnonyl) benzene-1,2 dicarboxylate (DIDP) and bis(2-ethylhexyl) benzene-1,2-dicarboxylate (DEHP) also showed comparable molecular interaction with enzymes of GBP. DPhP showed a significant molecular interaction with different enzymes of GBP such as CYP21A1, CYP11A1 and CYP11B2. These interactions mainly included H-bonding, hydrophobic, polar and van dar Waals' interactions. Interestingly, this in silico study revealed that certain PAEs have more inhibitory potential against enzymes of GBP than their respective known inhibitors. Such studies become more relevant in the risk assessment of exposure to mixtures of phthalate eaters. Copyright © 2016 John Wiley & Sons, Ltd.
众所周知，糖皮质激素（GCs）对新陈代谢、行为和免疫具有广泛影响。其合成和分泌受损会对健康产生不利影响。一些环境毒物，包括邻苯二甲酸酯（PAEs），与内分泌干扰有关。这些内分泌干扰化学物质（EDCs）还会导致肾上腺毒性以及GC生物合成及其功能的改变。我们使用Schrodinger Maestro 9.4的计算机模拟工具，对32种配体进行了分子对接研究，这些配体包括具有已知内分泌干扰潜力的PAEs，以及GC生物合成途径（GBP）的选定酶，如CYP11A1、CYP11B2、CYP19A1、CYP17A1、CYP21A2和3α/20β-HSD。将PAEs的结合亲和力与这些酶的已知抑制剂进行了比较。在PAEs中，二苯基苯-1,2-二羧酸酯（DPhP）对CYP21A1的对接分数最低，为-8.95616 kcal mol。此外，苄基丁基苯-1,2-二羧酸酯（BBzP）、双（7-甲基壬基）苯-1,2-二羧酸酯（DIDP）和双（2-乙基己基）苯-1,2-二羧酸酯（DEHP）与GBP的酶也表现出相当的分子相互作用。DPhP与GBP的不同酶如CYP21A1、CYP11A1和CYP11B2表现出显著的分子相互作用。这些相互作用主要包括氢键、疏水、极性和范德华相互作用。有趣的是，这项计算机模拟研究表明，某些PAEs对GBP的酶的抑制潜力比其各自已知的抑制剂更大。此类研究在邻苯二甲酸酯混合物暴露风险评估中变得更加重要。版权所有© 2016 John Wiley & Sons, Ltd.
