Sheikh Ishfaq A, Yasir Muhammad, Abu-Elmagd Muhammad, Dar Tanveer A, Abuzenadah Adel M, Damanhouri Ghazi A, Al-Qahtani Mohammed, Beg Mohd A
King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, 21589, Jeddah, Kingdom of Saudi Arabia.
Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
BMC Struct Biol. 2016 Sep 30;16(Suppl 1):15. doi: 10.1186/s12900-016-0067-3.
Currently, alternate plasticizers are used to replace phthalate plasticizers in children's toys, medical equipments and food packaging, due to the adverse effects of phthalate compounds on human health and laws prohibiting their use. Current information regarding the safety and potential adverse effects of alternate plasticizers is limited and recent studies have found alternate plasticizers to display similar characteristics to those observed in phthalate plasticizers. This study was undertaken to evaluate and predict the potential endocrine disrupting activity of the three most commonly used alternate plasticizers: di(2-ethylhexyl)terephthalate (DEHT), tris(2-ethylhexyl)trimellitate (TOTM), and diisononyl hexahydrophthalate (DINCH) against human sex hormone-binding globulin (SHBG) using in silico approaches.
The crystal structure of human SHBG (Id: 1D2S) was retrieved from Protein Data Bank. PubChem database was searched for the structures of alternate plasticizers, DEHT, TOTM, and DINCH. Docking was performed using Glide (Schrodinger) Induced Fit Docking module.
Induced Fit Docking of three alternate plasticizer compounds indicated that each of the three compounds fitted well into the steroid binding pocket of SHBG. Docking displays showed interactions of alternate plasticizers with 25-30 amino-acid residues of SHBG; 18-20 amino residues overlapped between the natural ligand, DHT, and the three compounds (commonality of 82-91 %). The hydrogen-bonding interaction of the amino-acid residue, Asn-82, of SHBG was also present in displays of DHT and all the three alternate phthalates. The binding affinity of all the three alternate phthalates was higher than DHT; maximum in DINCH followed by TOTM and DEHT.
Our results suggested that the three alternate plasticizers have potential to engage the important interacting residues of SHBG and thus interfere in its steroid homeostatic function.
目前，由于邻苯二甲酸酯类化合物对人体健康有不良影响且法律禁止其使用，人们使用替代增塑剂来取代儿童玩具、医疗设备和食品包装中的邻苯二甲酸酯类增塑剂。关于替代增塑剂安全性和潜在不良影响的现有信息有限，最近的研究发现替代增塑剂表现出与邻苯二甲酸酯类增塑剂相似的特性。本研究旨在使用计算机模拟方法评估和预测三种最常用的替代增塑剂：对苯二甲酸二（2-乙基己基）酯（DEHT）、偏苯三酸三（2-乙基己基）酯（TOTM）和六氢邻苯二甲酸二异壬酯（DINCH）对人性激素结合球蛋白（SHBG）的潜在内分泌干扰活性。
从蛋白质数据库中检索人SHBG（编号：1D2S）的晶体结构。在PubChem数据库中搜索替代增塑剂DEHT、TOTM和DINCH的结构。使用Glide（薛定谔）诱导契合对接模块进行对接。
三种替代增塑剂化合物的诱导契合对接表明，这三种化合物中的每一种都能很好地契合SHBG的类固醇结合口袋。对接显示表明替代增塑剂与SHBG的25 - 30个氨基酸残基相互作用；天然配体双氢睾酮（DHT）与这三种化合物之间有18 - 20个氨基酸残基重叠（共性为82 - 91%）。SHBG的氨基酸残基Asn - 82的氢键相互作用在DHT和所有三种替代邻苯二甲酸酯的显示中也存在。所有三种替代邻苯二甲酸酯的结合亲和力均高于DHT；DINCH最高，其次是TOTM和DEHT。
我们的结果表明，这三种替代增塑剂有可能与SHBG的重要相互作用残基结合，从而干扰其类固醇稳态功能。
