GABA受体抑制剂的定量构效关系研究
文献类型:学位论文
作者 | 沈斌 |
学位类别 | 硕士 |
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 | 任天瑞 |
关键词 | GABA受体抑制剂 三维定量构效关系(3D-QSAR) 农药 柔性原子受体模型 |
其他题名 | Studies on the Quantitative Structure-Activity Relationship GABA-Receptor Inhibitors |
学位专业 | 化学工艺 |
中文摘要 | GABA(γ-氨基丁酸)受体是农药、医药的重要作用靶标之一,对GABA受体激 动剂和抑制剂的构效关系研究,有助于新农药、新医药的开发。本论文用商业软件和 自己编制的程序分别研究了具有杀虫活性与医药活性2类化合物的构效关系,并改进 了柔性原子受体模型(Florm)的程序。具体研究内容和取得的结果包括:(1)对于具有杀虫活性的作用于GABA受体EBOB位点的化合物进行构效关系研究a.用DISCOtech方法分别建立了这类化合物与家蝇或者大鼠GABA受体作用的 两种药效团模型,具体地指出了每个模型中活性位点(feature)的基团特征和它们之 间的距离。b.用CoMFA方法进行了这类化合物与家蝇或者大鼠GABA受体作用的 3D-QSAR研究,模型的交叉验证相关系数分别为0.679、0.526;用CoMSIA方法建 立了这类化合物针对家蝇GABA受体的3D-QSAR模型,其交叉验证相关系数达到了 0.713。c.用柔性原子受体模型方法建立了有选择性的柔性原子受体模型,训练集的交 叉相关系数分别达到了0.874、0.897,预测集的传统相关系数也分别达到了0.962、 0.923,通过分析受体模型与配体分子的作用并结合与药效团模型的比较,发现这类 配体与受体作用可能具有5个活性因素,但是家蝇和大鼠相应的受体对这5个活性因 素要求却各有侧重点。(2)对具有医药活性的苯二氮卓类化合物进行构效关系研究用D工SCOtech方法建立了这类化合物的药效团模型,结合DISCOtech方法,用 coMFA、coMsIA、Florm方法建立了相应的QsAR模型,训练集的护分别达到0.609、 0.513、0.856,预测集的r2分别达到0.778、0.880、0.780。(3)对Flarm程序进行了改进用VC++6.0集成开发环境,将原来的柔性原子受体模型的建模程序进行了可视 化,多线程化,为程序建立了友好的用户界面,并运用线程同步技术使得程序在运行 时用户可以通过各种命令对遗传算法进行控制;并对Flarm的原子类型进行了改进, 将原来的33种配体原子类型发展到47种。本论文的研究结果可以为设计作用在GABA受体上的新农药、新医药提供理论 指导,Flarm程序的改进工作为新药设计提供了一个便捷的计算工具。 |
英文摘要 | γ-Aminobutyric acid (GABA) receptor is an important acting target in insecticidal and medicinal areas. The research of the structure-activity relationships of GABA receptor's agonists and inhibitors is an available approach for developing new insecticides and medicine. The quantitative structure-activity relationships(QSAR) in two kinds of compounds were studied by using commercial software and a self-compiled program, with insecticidal and medicinal activity respectively. The program of Flarm was improved. Research content and results are expressed as follows:(1)The QSAR studies on the insecticidal compounds that act on EBOB site of GABA receptors a.The different pharmacophore models were built using DISCOtech for fly or rat GABA-receptor inhibitors. The model features presented the activity sites and the distances between them. b.The 3D-QSAR models were built by CoMFA method for the compounds binding with the GABA receptors of rat and fly. The q2 values of the CoMFA models were 0.679 and 0.526 respectively. The CoMSIA model was built for the compounds binding with the GABA receptor of fly, the Rvalue of the model was 0.713. c.The selective Flarm models were built for the compounds. The q2 values of the training sets were 0.874 and 0.897, the r2 values of the predict sets were 0.962 and 0.923. The Flarm models proposed that there must be five binding sites when the compounds binding with GABA receptors, but there might be some different preferences between the GABA receptors of fly and rat. (2)The QSAR studies on the medicinal benzodiazepines The pharmacophore model was built by DISCOtech method for the benzodiazepines binding with GABA receptor at a site different from the EBOB site. Based on the DISCOtech model, CoMFA, CoMSIA and Flarm models were build for the benzodiazepines, the q1 values of the training set were 0.609, 0.513 and 0.856, the r2 values of the predict set were 0.778,0.880 and 0.780, respectively. (3) The improvement of the Flarm program The Flarm program was improved with VC++6.0. The user interface was added to the program for people controlling the calculation progress. The thread-synchronize technology was applied in the new program, and the number of the ligand-atom type was developed from 33 to 47. The research results will lead to the design of new pesticide and medicine. The improvement of Flarm program distributed a user-friendly program for drug design. |
语种 | 中文 |
公开日期 | 2013-09-16 |
页码 | 86 |
源URL | [http://ir.ipe.ac.cn/handle/122111/1395] ![]() |
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 | 沈斌. GABA受体抑制剂的定量构效关系研究[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。