Synthesis of Novel Nitrogen-Containing Heterocycle Bromophenols and Their Interaction with Keap1 Protein by Molecular Docking
Synthesis of Novel Nitrogen-Containing Heterocycle Bromophenols and Their Interaction with Keap1 Protein by Molecular Docking
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新型含氮杂环溴酚的合成及其与Keap1蛋白的分子对接相互作用
DOI：
10.3390/molecules22122142
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发表时间：
2017-12-01
期刊：
影响因子：
4.6
通讯作者：
Li, Qing Shan
中科院分区：
文献类型：
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作者：
Feng, Xiu E.;Wang, Qin Jin;Li, Qing Shan
我们之前报道了5,2'-二溴-2,4',5'-三羟基二苯甲烷（LM49），一种溴酚类似物，由于其优越的抗炎，抗氧化和抗凋亡特性，显示出对氧化应激损伤的强保护作用。本文通过引入取代哌啶、哌嗪和咪唑修饰前导化合物LM49的2位，合成了一系列新型含氮杂环溴苯酚。通过进一步评估其对EA.hy926细胞H2O2损伤的细胞保护活性，14种靶溴酚表现出中效至强效活性，EC50值在0.9 ~ 6.3 M之间，强于阳性参比化合物槲皮素（EC50值：18.0 M）。其中，最有效的化合物22b是哌嗪溴酚，EC50值为0.9 M，相当于LM49。随后进行分子对接研究，推断衍生卤酚类化合物对Keap1 Kelch结构域的亲和力和结合方式，对接结果表明，小分子22b通过稳定的氢键和疏水相互作用被Keap1-Kelch和Nrf2的结合区很好地容纳，从而增强了配体与受体之间的亲和力和稳定性。上述事实表明，22b是一个有希望进一步开发心血管药物的药理候选者。此外，靶向Keap1-Nrf2蛋白-蛋白相互作用可能是卤素酚选择性和有效激活Nrf2触发下游保护基因防御损伤的一种新兴策略。
We previously reported 5,2'-dibromo-2,4',5'-trihydroxydiphenylmethanoe (LM49), a bromophenol analogue that shows strong protection from oxidative stress injury owing to its superior anti-inflammatory, antioxidant, and anti-apoptotic properties. A series of novel nitrogen-containing heterocycle bromophenols were herein synthesized by introducing substituted piperidine, piperazine, and imidazole to modify 2-position of the lead compound LM49. By further evaluating their cytoprotective activity against H2O2 induced injury in EA.hy926 cells, 14 target bromophenols showed moderate-to-potent activity with EC50 values in the range of 0.9-6.3 M, which were stronger than that of quercetin (EC50: 18.0 M), a positive reference compound. Of these, the most potent compound 22b is a piperazine bromophenol with an EC50 value of 0.9 M equivalent to the LM49. Molecular docking studies were subsequently performed to deduce the affinity and binding mode of derived halophenols toward the Keap1 Kelch domain, the docking results exhibited that the small molecule 22b is well accommodated by the bound region of Keap1-Kelch and Nrf2 through stable hydrogen bonds and hydrophobic interaction, which contributed to the enhancement of affinity and stability between the ligand and receptor. The above facts suggest that 22b is a promising pharmacological candidate for further cardiovascular drug development. Moreover, the targeting Keap1-Nrf2 protein-protein interaction may be an emerging strategy for halophenols to selectively and effectively activate Nrf2 triggering downstream protective genes defending against injury.