穿心莲内酯衍生物抑制糖苷酶的3D-QSAR及多羟基酚类化合物的抗氧化理论研究
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摘要
本文的研究工作分为两个部分，第一部分研究了新型穿心莲内酯类衍生物抑制α-葡萄糖苷酶活性的三维定量构效关系(3D-QSAR)，建立了糖和糖苷酶抑制剂数据库。第二部分讨论了白英中化学成分的提取分离和结构鉴定，研究了白英提取物中多羟基酚类化合物的结构与抗氧化活性的关系。
一．新型穿心莲内酯衍生物抑制α-葡萄糖苷酶的3D-QSAR研究
在测定穿心莲内酯衍生物的α-葡萄糖苷酶的抑制活性时，使用的α-葡萄糖苷酶的三维晶体结构还未见报道，所以选用同源建模的方法来构建该α-葡萄糖苷酶的三维结构。首先在NCBI的GenBank数据库中查得该α-葡萄糖苷酶的氨基酸序列，它由584个氨基酸构成。用蛋白质多序列比对程序BLAST在PDB数据库中进行序列相似性搜索，获得序列同源性达38％的蛋白1UOK。使用Insight Ⅱ软件中的Modeler模块以1UOK为模板对实验使用的α-葡萄糖苷酶进行同源模建。使用Profile-3D模块对已构建的α-葡萄糖苷酶的三维结构模型进行可靠性分析，发现模板与模建分子的α碳原子之间的标准偏差为0.42(?)，构建的三维结构得分为237.9分，远远高于临界得分120.2分，略低于理想得分267.2分。因此，说明模建得到的α-葡萄糖苷酶的三维结构在现有理论水平下是可靠的。使用Binding Site模块对蛋白的活性位点进行分析。使用Cerius~2软件的LigandFit模块完成穿心莲内酯衍生物与α-葡萄糖苷酶的对接，讨论了它们之间的相互作用模式，研究表明，形成氢键和静电相互作用是抑制剂与受体相互作用的重要特征。利用Cerius~2软件中的QSAR模块获得了穿心莲内酯衍生物抑制α-葡萄糖苷酶的三维定量构效关系(3D-QSAR)，通过MFA分析得到的QSAR方程的交叉验证相关系数为0.901，常规相关系数为0.996，说明方程的可信度相当高。该研究为设计新型穿心莲内酯类α-葡萄糖苷酶抑制剂提供了有力的帮助。
基于MDL ISIS／BASE数据库平台，建立了糖和糖苷酶抑制剂穿心莲内酯衍生物分子数据库，已收录糖分子288、穿心莲内酯衍生物238，以利于新合成化合物的分类，虚拟筛选，综合利用。
二．白英中化学成分的提取分离及提取物中多羟基酚类化合物的结构与抗氧化活性的关系研究
对白英采用系统溶剂提取法对其化学成分进行了提取。选用乙醇为提取溶剂，乙醇提取液浓缩成浸膏，依次用氯仿、乙酸乙酯、正丁醇萃取。对萃取得到的浸膏采用葡聚糖LH-20、硅胶柱层析和制备薄层层析进行分离纯化，乙酸乙酯部位和正丁醇部位各分得化合物4个，经波谱(NMR、MS、IR)方法鉴定了它们的结构，分别为3-甲氧基-5-[(8′S)-3′-甲氧基-4′-羟基-苯丙醇]-E-苯丙烯醇-4-O-β-D-葡萄糖苷、芹菜素
This thesis consists of two parts. The first part deals with the 3D-QSAR studies on andrographolide derivatives inhibiting α-glucosidase and foundation of the database of glucides and inhibitors of glucosidase. The second part includes discussions on extraction processes, separation methods and structural identifications of chemical constituents in Solynum Larytum Thunb., as well as studies on the structure-activity relationship of the polyhydroxyphenol compounds in Solarium Lyratum Thunb. I. The 3D-QSAR studies on andrographolide derivatives inhibiting α-glucosidase
So far there have been no reports on the three-dimensional structure of the a-glucosidase, which has been used in the test of the inhibiting its activity by andrographolide derivatives, it is important to build the three-dimensional structure of the a-glucosidase with the homology methods. The sequence of a-glucosidase was obtained from the databank of the National Center for Biotechnology Information (NCBI code: P38158), and it is composed of 584 amino acids. The homology was searched from the PDB databank with BLAST program, and 1U0K was found. Their sequence identity between 1U0K and a-glucosidase is as high as 38%. The Modeler module of the Insight II software was used to build the a-glucosidase model. The final structure was further checked with Profile-3D, and root mean square deviation (RMSD) value between 1U0K and P38158 is 0.42 A. The self-compatibility score for this protein is 237.9 which is higher than the low score 120.2 and close to the top score 267.2. The above results indicate that the homology model is reliable in the current test standard. Protein active sites were analyzed by the Binding Site module. Then, we docked andrographolide derivatives into a-glucosidase with the LigandFit module of the Cerius2 software, investigated their interaction modes. This study suggests that hydrogen bonding and electrostatic interaction are the important characteristic of the interaction between the inhibitors and the a-glucosidase. In the end, three-dimensional quantitative structure- activity relationship(3D-QSAR) between andrographolide derivatives and a-glucosidase was established with the QSAR module. The QSAR model was generated by using MFA method, which has a r2cv (cross-validated) of 0.901 while its r2 (conventional) value is 0.996. The higher r2cv and r2 show that QSAR model is reliable. The conclusions of this study will
一．新型穿心莲内酯衍生物抑制α-葡萄糖苷酶的3D-QSAR研究
在测定穿心莲内酯衍生物的α-葡萄糖苷酶的抑制活性时，使用的α-葡萄糖苷酶的三维晶体结构还未见报道，所以选用同源建模的方法来构建该α-葡萄糖苷酶的三维结构。首先在NCBI的GenBank数据库中查得该α-葡萄糖苷酶的氨基酸序列，它由584个氨基酸构成。用蛋白质多序列比对程序BLAST在PDB数据库中进行序列相似性搜索，获得序列同源性达38％的蛋白1UOK。使用Insight Ⅱ软件中的Modeler模块以1UOK为模板对实验使用的α-葡萄糖苷酶进行同源模建。使用Profile-3D模块对已构建的α-葡萄糖苷酶的三维结构模型进行可靠性分析，发现模板与模建分子的α碳原子之间的标准偏差为0.42(?)，构建的三维结构得分为237.9分，远远高于临界得分120.2分，略低于理想得分267.2分。因此，说明模建得到的α-葡萄糖苷酶的三维结构在现有理论水平下是可靠的。使用Binding Site模块对蛋白的活性位点进行分析。使用Cerius~2软件的LigandFit模块完成穿心莲内酯衍生物与α-葡萄糖苷酶的对接，讨论了它们之间的相互作用模式，研究表明，形成氢键和静电相互作用是抑制剂与受体相互作用的重要特征。利用Cerius~2软件中的QSAR模块获得了穿心莲内酯衍生物抑制α-葡萄糖苷酶的三维定量构效关系(3D-QSAR)，通过MFA分析得到的QSAR方程的交叉验证相关系数为0.901，常规相关系数为0.996，说明方程的可信度相当高。该研究为设计新型穿心莲内酯类α-葡萄糖苷酶抑制剂提供了有力的帮助。
基于MDL ISIS／BASE数据库平台，建立了糖和糖苷酶抑制剂穿心莲内酯衍生物分子数据库，已收录糖分子288、穿心莲内酯衍生物238，以利于新合成化合物的分类，虚拟筛选，综合利用。
二．白英中化学成分的提取分离及提取物中多羟基酚类化合物的结构与抗氧化活性的关系研究
对白英采用系统溶剂提取法对其化学成分进行了提取。选用乙醇为提取溶剂，乙醇提取液浓缩成浸膏，依次用氯仿、乙酸乙酯、正丁醇萃取。对萃取得到的浸膏采用葡聚糖LH-20、硅胶柱层析和制备薄层层析进行分离纯化，乙酸乙酯部位和正丁醇部位各分得化合物4个，经波谱(NMR、MS、IR)方法鉴定了它们的结构，分别为3-甲氧基-5-[(8′S)-3′-甲氧基-4′-羟基-苯丙醇]-E-苯丙烯醇-4-O-β-D-葡萄糖苷、芹菜素
This thesis consists of two parts. The first part deals with the 3D-QSAR studies on andrographolide derivatives inhibiting α-glucosidase and foundation of the database of glucides and inhibitors of glucosidase. The second part includes discussions on extraction processes, separation methods and structural identifications of chemical constituents in Solynum Larytum Thunb., as well as studies on the structure-activity relationship of the polyhydroxyphenol compounds in Solarium Lyratum Thunb. I. The 3D-QSAR studies on andrographolide derivatives inhibiting α-glucosidase
So far there have been no reports on the three-dimensional structure of the a-glucosidase, which has been used in the test of the inhibiting its activity by andrographolide derivatives, it is important to build the three-dimensional structure of the a-glucosidase with the homology methods. The sequence of a-glucosidase was obtained from the databank of the National Center for Biotechnology Information (NCBI code: P38158), and it is composed of 584 amino acids. The homology was searched from the PDB databank with BLAST program, and 1U0K was found. Their sequence identity between 1U0K and a-glucosidase is as high as 38%. The Modeler module of the Insight II software was used to build the a-glucosidase model. The final structure was further checked with Profile-3D, and root mean square deviation (RMSD) value between 1U0K and P38158 is 0.42 A. The self-compatibility score for this protein is 237.9 which is higher than the low score 120.2 and close to the top score 267.2. The above results indicate that the homology model is reliable in the current test standard. Protein active sites were analyzed by the Binding Site module. Then, we docked andrographolide derivatives into a-glucosidase with the LigandFit module of the Cerius2 software, investigated their interaction modes. This study suggests that hydrogen bonding and electrostatic interaction are the important characteristic of the interaction between the inhibitors and the a-glucosidase. In the end, three-dimensional quantitative structure- activity relationship(3D-QSAR) between andrographolide derivatives and a-glucosidase was established with the QSAR module. The QSAR model was generated by using MFA method, which has a r2cv (cross-validated) of 0.901 while its r2 (conventional) value is 0.996. The higher r2cv and r2 show that QSAR model is reliable. The conclusions of this study will
引文
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