抗2型糖尿病药物设计方法研究
文献类型：学位论文
| 作者 | 廖晨钟 |
| 学位类别 | 博士 |
| 答辩日期 | 2004 |
| 授予单位 | 中国科学院过程工程研究所 |
| 授予地点 | 中国科学院过程工程研究所 |
| 导师 | 周家驹 |
| 关键词 | 胰岛素增敏剂 计算机辅助药物设计 药物发现 三维定量结构活性关系 虚拟组合化学库 虚拟筛选 |
| 其他题名 | The Design Method Studies of Anti Type 2 Diabetic Drugs |
| 中文摘要 | 代谢综合症包括2型糖尿病以及相关的并发症，如肥胖、心血管疾病、高血压、异常脂血症等，这些疾病对人们的日常生活带来了相当大的影响。近年来发现2型糖尿病与过氧化物酶增殖体活化受体（peroxisome proliferator-activated receptor，PPAR）存在着密切的联系，因而该受体成为设计抗2型糖尿病药物的主要靶点之一。以PPAY为作用靶点的新型药物胰岛素增敏剂虽然疗效显著，但存在着引起贫血、水肿、肥胖和心衰等不良反应。本论文以PPAR为靶点，通过多种药物设计方法，试图获得能克服现有胰岛素增敏剂固有不良反应的PPARa／γ 激活剂和PPARa/γ/δ共激活剂，包括以下几个方面工作的内容。（1）考察PPAR与小分子配体的相互作用，研究药物结合部位的结构与性质，为设计抗2型糖尿病药物提供理论指导。并在此基础上提出了以PPAR为靶标的抗2型糖尿病药物的研发策略。（2）采用比较分子力场分析法（CoMFA），以及近年新出现的比较分子相似因子分析法（CoMSIA）和本征值方法（EVA）建立了PPARγ激活剂的三维定量结构活性关系（3D QSAR）模型。（3）针对PPAR3种受体亚型配体的结构特征，用SMILES码代表骨架和支链分子碎片，建立了一个三维的抗2型糖尿病药物虚拟组合化学库（A2DDVCL）。该库在用设置的过滤条件初筛后，包含1，226，625个虚拟化合物。用DOCK 4.0程序对该库进行虚拟筛选，其最终目的是为了发现能治疗2型糖尿病及其他与PPAR相关的代谢疾病的药物。用Visual Basic.net实现了用SMILES码构建虚拟库的通用方法。（4）以PPARγ为靶点，用DoCK4.0程序搜索小分子有机化合物数据库，用以发现新型抗2型糖尿病药物。使用的数据库包括化学结构数据库，天然产物数据库以及上述的抗2型糖尿病药物虚拟组合化学库。根据特定体系，拟合了一条分析虚拟筛选数据的指数递减函数，从而修正分子量对筛选结果的影响，以减轻数据分析工作。在此基础上，根据蛋白质IFM9的晶体结构特征提出了一套分析虚拟筛选结果的方法。（5）最后介绍了根据“me-too”或“me-better”原则设计的部分抗2型糖尿病药物，包括它们在药物合成、体外活性测试和体内活性测试等方面的实验方法和结果。 |
| 英文摘要 | The chronic metabolic syndrome includes type 2 diabetes and related complications, such as obesity, cardiovascular diseases, hypertension, and dyslipidemia, etc, which have seriously affected people's daily life. In recent years, it was found that type 2 diabetes has intimate relationship with peroxisome proliferator-activated receptor (PPAR), a nuclear receptor, so PPAR has become a focused target for designing anti type 2 diabetic drugs. A class of compounds termed thiazolidinedione (TZD) has been developed as treatment for type 2 diabetes to reduce hyperglycemia by promoting insulin action, but the side effects such as obesity, edema, and anemia in treated patients further hamper their extended use in the management of the diseases. This thesis has adopted several different methods of drug design to employ PPAR as target to get PP ARa/y dual agonists and/or PPARa/y/8 triple agonists which maybe prevent the side effects of the developed insulin sensitizer. The thesis includes the following works. We have investigated the interactions between PPAR and small molecules to get information about the physical chemical properties of 3 different PPAR subtypes' ligand binding domains (LBD). This information is very useful when designing PPAR's ligands. CoMFA (comparative molecular field analysis), CoMSIA (comparative molecular similarity indices analysis) and EVA (eigen value analysis) have been employed on a series of potent agonists of PPARy in this article. At last predictive CoMFA, CoMSIA and EVA quantitative structure-activity relationship (QSAR) models were established using the SYBYL package. Based on the structural characters of PPAR modulators, a virtual combinatorial library containing 1,226,625 compounds was constructed using SMILES strings. Selected ADME filters were employed to compel compounds having poor drug-like properties from this library. This library was converted to sdf and mol2 files by CONCORD 4.0, and was then docked to PPARy by DOCK 4.0 to identify new chemical entities that may be potential drug leads against type 2 diabetes and other metabolic diseases. The method to construct virtual combinatorial library using SMILES strings was further visualized by Visual Basic.net that can facilitate the needs of generating other type virtual combinatorial libraries. Virtual screening methods were employed to get new chemical entities for the management of type 2 diabetes and its complications. The docking programs used include DOCK 4.0, AutoDock 3.05 and FlexX. Based on the given system, we have fitted a degressive exponential equation to weaken the influence of heavy atoms number to data analysis. At last, some anti type 2 diabetic drugs based on other success paradigm ("me-too" or "me-better" principle) has been introduced. And the methods and results about their synthesis, in vitro and in vivo tests also have been presented in this thesis. |
| 语种 | 中文 |
| 公开日期 | 2013-09-16 |
| 页码 | 172 |
| 源URL | [http://ir.ipe.ac.cn/handle/122111/1419]  |
| 专题 | 过程工程研究所_研究所（批量导入） |
| 推荐引用方式 GB/T 7714 | 廖晨钟. 抗2型糖尿病药物设计方法研究[D]. 中国科学院过程工程研究所. 中国科学院过程工程研究所. 2004. |
入库方式： OAI收割
来源：过程工程研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。