醛糖还原酶抑制剂筛选及姜黄素类似物抗癌活性三维定量构效关系研究
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摘要
醛糖还原酶(Aldose Reductase, AR或ALR2)是多元醇通路中的一个关键限速酶,与糖尿病并发症发生与发展密切相关,近年研究还证实其与炎症反应密切相关。先前开发的醛糖还原酶抑制剂(Aldose Reductase Inhibitor, ARI)由于对醛糖还原酶(ALR2)与其同源酶-醛还原酶(ALR1)的选择性较差,使其存在毒副作用而导致临床效果不理想。本论文主要涉及：(1)从天然产物库及抗炎药物数据库中虚拟筛选ARI,并进行了选择性的虚拟筛选。(2)从姜黄素类似物筛选ARI,并研究其抗炎作用。(3)由于姜黄素类似物具有良好的抗肿瘤活性,本论文在前期的研究基础上,研究姜黄素类似物对肿瘤细胞株的细胞毒的三维定量构效关系。
本论文首先利用分子对接工具,基于含有四万余个天然产物化合物库及抗炎药物数据库,对ALR2进行ARI虚拟筛选,并利用ALR1晶体进行了对ALR1抑制作用的二次选择性虚拟筛选。以ALR2受体进行天然产物数据库虚拟筛选,分数高于7.5分化合物一共127个,并讨论其构效关系及进行选择性抑制筛选,对ARI的选择性抑制机理进行了探讨,为后续开发新型天然ARI打下了基础。在抗炎药物虚拟筛选中,发现了两个具有潜力的非甾体抗炎药物,其中一种与已报道的系列ARI结构较为相似。
在对姜黄素类似物进行AR活性测试中,使用表达人类醛糖还原酶筛选得到抑制活性较好的A2化合物；其在后续抗炎实验中展现了较好的抗炎活性。巨噬细胞MTT实验中,A2在5μM时已经达到半数抑制率,且统计学具有显著性差异；在建立由佛波酯诱导的小鼠耳朵局部炎症模型中,A2可以有效抑制炎症反应,小鼠耳朵组织荧光切片观察及耳洞重量都具有显著性差异；利用ELISA对巨噬细胞及小鼠耳朵组织的白细胞介素-1p水平进行了研究,5μM浓度时A2可以将白细胞介素-1p水平降低到阳性对照组的25%以下。
另外,基于44个姜黄素类似物对Panc-1、HT-29肿瘤细胞株的抗癌活性数据,使用CoMFA方法分别建立3D-QSAR模型,模型q2分别为0.580和0.722,所建立的3D-QSAR模型确实具有较高的统计学意义。同时运用此QSAR模型,成功设计预测了一系列新型姜黄素类似物,在此基础上合成的S14、S31、S22化合物在抗癌活性测试中表现出非常好的抗癌活性。
Aldose Reductase (AR or ALR2) is the key enzyme in the polyol pathway that play a key role in the diabetes complications, which also has been confirmed relate to the inflammatory signals mediation. For the aldose reductase is closed to its homologous enzyme aldehyde reductase, previous Aldose Reductase inhibitors (ARIs) lack of the highly specifically selective to ALR2, which made the ARIs had serious side effects and unsatisfactory clinical results. This thesis mainly involes the screening of ARIs from natural product database, anti-inflammatory drugs database and curcumin analogues, which contained the focus on the anti-inflammatory effect of curcumin analogues. We also used the three dimensional quantitative structure-actiity relationship (3D-QSAR) to study the curcumin analogues antitumor cells based the previously research.
We used of the molecular docking tools to virtual screening of the ARIs based on the natural product database contained over forty thousand natural products and the anti-inflammatory drugs database. To obtain the highly specifically selective ARIs, we used the screening compounds to run the molecule docking to ALR1protein. During the screening process, total127compounds'scores higher than7.5points, its structure-actiity relationship have been discussed and its selective inhibition have been screening, which could help the development of novel natural ARIs. In the anti-inflammatory drugs virtual screening, two potential non-steroidal anti-inflammatory drugs have been found, and one drug was similar to the serie ARI structures has reported.
In the AR inhibition assay of curcumin analogues which used the gene engineering expression ALR2, A2showed the strong activity against ALR2, and A2also performance well in the anti-inflammatory experiments. In the Macrophages MTT assay, A2in5μM has reach half inhibition rate, and had statistic significant difference. In the TPA induced mouse ear edema and mouse skin model, A2could effectively reduce the inflammation, which was confirmed by the mouse ears organization fluorescence slice observation and ear hole weight has significant difference. In the IL-1β ELISA assay, A2could reduce IL-1β to25%at5μM. In addition, we established the3D-QSAR model based on the Panc-1, HT-29tumor cell MTT data by CoMFA method, its q2was0.580and0.722respectively. Used this model successfully predicted a novel serie of curcumin analogues, and S14, S31, S22exhibited the very good anti-cancer activity against tumor cell.
本论文首先利用分子对接工具,基于含有四万余个天然产物化合物库及抗炎药物数据库,对ALR2进行ARI虚拟筛选,并利用ALR1晶体进行了对ALR1抑制作用的二次选择性虚拟筛选。以ALR2受体进行天然产物数据库虚拟筛选,分数高于7.5分化合物一共127个,并讨论其构效关系及进行选择性抑制筛选,对ARI的选择性抑制机理进行了探讨,为后续开发新型天然ARI打下了基础。在抗炎药物虚拟筛选中,发现了两个具有潜力的非甾体抗炎药物,其中一种与已报道的系列ARI结构较为相似。
在对姜黄素类似物进行AR活性测试中,使用表达人类醛糖还原酶筛选得到抑制活性较好的A2化合物；其在后续抗炎实验中展现了较好的抗炎活性。巨噬细胞MTT实验中,A2在5μM时已经达到半数抑制率,且统计学具有显著性差异；在建立由佛波酯诱导的小鼠耳朵局部炎症模型中,A2可以有效抑制炎症反应,小鼠耳朵组织荧光切片观察及耳洞重量都具有显著性差异；利用ELISA对巨噬细胞及小鼠耳朵组织的白细胞介素-1p水平进行了研究,5μM浓度时A2可以将白细胞介素-1p水平降低到阳性对照组的25%以下。
另外,基于44个姜黄素类似物对Panc-1、HT-29肿瘤细胞株的抗癌活性数据,使用CoMFA方法分别建立3D-QSAR模型,模型q2分别为0.580和0.722,所建立的3D-QSAR模型确实具有较高的统计学意义。同时运用此QSAR模型,成功设计预测了一系列新型姜黄素类似物,在此基础上合成的S14、S31、S22化合物在抗癌活性测试中表现出非常好的抗癌活性。
Aldose Reductase (AR or ALR2) is the key enzyme in the polyol pathway that play a key role in the diabetes complications, which also has been confirmed relate to the inflammatory signals mediation. For the aldose reductase is closed to its homologous enzyme aldehyde reductase, previous Aldose Reductase inhibitors (ARIs) lack of the highly specifically selective to ALR2, which made the ARIs had serious side effects and unsatisfactory clinical results. This thesis mainly involes the screening of ARIs from natural product database, anti-inflammatory drugs database and curcumin analogues, which contained the focus on the anti-inflammatory effect of curcumin analogues. We also used the three dimensional quantitative structure-actiity relationship (3D-QSAR) to study the curcumin analogues antitumor cells based the previously research.
We used of the molecular docking tools to virtual screening of the ARIs based on the natural product database contained over forty thousand natural products and the anti-inflammatory drugs database. To obtain the highly specifically selective ARIs, we used the screening compounds to run the molecule docking to ALR1protein. During the screening process, total127compounds'scores higher than7.5points, its structure-actiity relationship have been discussed and its selective inhibition have been screening, which could help the development of novel natural ARIs. In the anti-inflammatory drugs virtual screening, two potential non-steroidal anti-inflammatory drugs have been found, and one drug was similar to the serie ARI structures has reported.
In the AR inhibition assay of curcumin analogues which used the gene engineering expression ALR2, A2showed the strong activity against ALR2, and A2also performance well in the anti-inflammatory experiments. In the Macrophages MTT assay, A2in5μM has reach half inhibition rate, and had statistic significant difference. In the TPA induced mouse ear edema and mouse skin model, A2could effectively reduce the inflammation, which was confirmed by the mouse ears organization fluorescence slice observation and ear hole weight has significant difference. In the IL-1β ELISA assay, A2could reduce IL-1β to25%at5μM. In addition, we established the3D-QSAR model based on the Panc-1, HT-29tumor cell MTT data by CoMFA method, its q2was0.580and0.722respectively. Used this model successfully predicted a novel serie of curcumin analogues, and S14, S31, S22exhibited the very good anti-cancer activity against tumor cell.
引文
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