BACKGROUND 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. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION 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.

中文翻译：

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人类性激素结合球蛋白作为替代增塑剂的潜在目标：计算机模拟研究。

背景技术当前，由于邻苯二甲酸酯化合物对人类健康的不利影响以及禁止使用它们的法律，替代的增塑剂被用于代替儿童玩具，医疗设备和食品包装中的邻苯二甲酸酯的增塑剂。关于替代增塑剂的安全性和潜在不利影响的当前信息是有限的，并且最近的研究发现替代增塑剂表现出与邻苯二甲酸酯增塑剂相似的特性。进行这项研究是为了评估和预测三种最常用的替代增塑剂的潜在内分泌干扰活性：二（2-乙基己基）对苯二甲酸酯（DEHT），三（2-乙基己基）三甲酸酯（TOTM）和六氢邻苯二甲酸二异壬酯使用计算机模拟方法来对抗人类性激素结合球蛋白（SHBG）。材料与方法人SHBG（Id：1D2S）的晶体结构是从Protein Data Bank中检索到的。在PubChem数据库中搜索了替代增塑剂DEHT，TOTM和DINCH的结构。使用Glide（Schrodinger）诱导拟合对接模块执行对接。结果三种替代增塑剂化合物的诱导对接研究表明，这三种化合物中的每一种都很好地适合SHBG的类固醇结合口袋。对接展示显示替代增塑剂与SHBG的25-30个氨基酸残基相互作用。18-20个氨基残基在天然配体DHT和这三种化合物之间重叠（通用度为82-91％）。SHBG氨基酸残基Asn-82的氢键相互作用也存在于DHT和所有三种交替的邻苯二甲酸酯的展示中。三种邻苯二甲酸酯的结合亲和力均高于DHT。在DINCH中最大，其次是TOTM和DEHT。结论我们的结果表明，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。