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Molecular docking and simulation analysis for elucidation of toxic effects of dicyclohexyl phthalate (DCHP) in glucocorticoid receptor-mediated adipogenesis
Molecular Simulation ( IF 1.9 ) Pub Date : 2019-09-02 , DOI: 10.1080/08927022.2019.1662002
Neha Singh 1 , Vikram Dalal 1 , Pravindra Kumar 1
Affiliation  

ABSTRACT ‘Obesogens’ are chemical agents that improperly regulate the genes involved in glucose metabolism and adipocyte differentiation and promote lipid accumulation and adipogenesis. The human glucocorticoid receptor (hGR) is a steroid hormone triggered transcriptional factor and regulates target genes important in basal glucose homeostasis. Molecular docking analysis was performed in order to assess in-silico structure based toxic effects of high molecular weight phthalates dicyclohexyl phthalate (DCHP) and its monophthalate metabolite mono-cyclohexyl phthalate (MCHP). Molecular docking results show that the binding affinities of DCHP and MCHP lie in the comparable range (−7.87 kcal/mol and −6.24 kcal/mol) with Dexamethasone (−10.2 kcal/mol), a potent agonist for hGR. These two PAEs occupy the active site of hGR and interact with the key residues. Molecular simulation results infer that hGR-PAEs complexes were stable. Density functional theory (DFT) analysis indicates that HOMO and LUMO energy gap of DCHP (3.88 eV) and MCHP (3.39 eV) are comparable to DEX (4.69 eV). Binding free energy calculations of the DCHP-hGR and MCHP-hGR complexes were estimated by using Molecular Mechanic/Poisson-Boltzmann Surface Area (MMPBSA) method. Molecular Docking and simulation results emphasise that DCHP and MCHP can efficiently bind to hGR, which further leads to glucocorticoid-mediated adipogenesis in a synergistic manner.

中文翻译:

分子对接和模拟分析阐明邻苯二甲酸二环己酯 (DCHP) 在糖皮质激素受体介导的脂肪生成中的毒性作用

摘要“肥胖素”是一种化学制剂,它不正确地调节参与葡萄糖代谢和脂肪细胞分化的基因,并促进脂质积累和脂肪生成。人类糖皮质激素受体 (hGR) 是一种类固醇激素触发的转录因子,可调节对基础葡萄糖稳态很重要的靶基因。进行分子对接分析以评估高分子量邻苯二甲酸酯邻苯二甲酸二环己酯 (DCHP) 及其单邻苯二甲酸酯代谢物邻苯二甲酸单环己酯 (MCHP) 的基于硅结构的毒性作用。分子对接结果表明,DCHP 和 MCHP 的结合亲和力与地塞米松 (-10.2 kcal/mol)(一种有效的 hGR 激动剂)处于可比范围(-7.87 kcal/mol 和 -6.24 kcal/mol)。这两个 PAE 占据 hGR 的活性位点并与关键残基相互作用。分子模拟结果推断 hGR-PAEs 复合物是稳定的。密度泛函理论 (DFT) 分析表明 DCHP (3.88 eV) 和 MCHP (3.39 eV) 的 HOMO 和 LUMO 能隙与 DEX (4.69 eV) 相当。DCHP-hGR 和 MCHP-hGR 复合物的结合自由能计算通过使用分子力学/泊松-玻尔兹曼表面积 (MMPBSA) 方法进行估计。分子对接和模拟结果强调 DCHP 和 MCHP 可以有效地与 hGR 结合,从而进一步以协同方式导致糖皮质激素介导的脂肪生成。39 eV) 与 DEX (4.69 eV) 相当。DCHP-hGR 和 MCHP-hGR 复合物的结合自由能计算通过使用分子力学/泊松-玻尔兹曼表面积 (MMPBSA) 方法进行估计。分子对接和模拟结果强调 DCHP 和 MCHP 可以有效地与 hGR 结合,从而进一步以协同方式导致糖皮质激素介导的脂肪生成。39 eV) 与 DEX (4.69 eV) 相当。DCHP-hGR 和 MCHP-hGR 复合物的结合自由能计算通过使用分子力学/泊松-玻尔兹曼表面积 (MMPBSA) 方法进行估计。分子对接和模拟结果强调 DCHP 和 MCHP 可以有效地与 hGR 结合,从而进一步以协同方式导致糖皮质激素介导的脂肪生成。
更新日期:2019-09-02
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