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Research and Development of Drug Design Based on Three-Dimensional and Dynamic Structural Change in Molecular Recognition Process.

基于分子识别过程中三维动态结构变化的药物设计研究与进展。

基本信息

批准号：
11672215
负责人：
CHUMAN Hiroshi
金额：
$ 2.24万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

From a viewpoint of dynamic and three-dimensional structural change in drug- receptor interaction process, we have carried out the following three model studies for the aims of understanding the interaction and its application to rational drug design, 1. A novel Quantitative Structure-Activity Relationship (QSAR) analyses of a series of bioactive molecules, 2. Experimental approach for the drug-receptor interaction, and 3. Dynamic modeling of a drug-receptor model.1. We have developed a novel three-dimensional QSAR procedure based on the Voronoi polyhedral division. Insecticidal pyrethroids molecules have structural and conformational diversity, and are difficult to be comprehensively understood by conventional QSAR procedures. We have been successful in a comprehensive understanding of QSAR of pyrethroids by a combined approach of our developed QSAR and the exhaustive conformational analyses.2. We have measured the quantitative magnitudes of the molecular interaction between concanavalin A and various carbohydrates using an optical biosensor utilizing a surface plasmon resonance technique, and constructed a SAR model. We are now preparing to analyze the interaction quantitatively at atomic resolved level, referring to the X-ray crystallographic result of the complex between α-methyl-Mannose and concanavalin A.3. As a model of time-dependent dynamic drug-receptor interaction process, we have carried out molecular dynamics computation for the interaction between ATP/ADP carrier protein and ATP, ADP, GTP, and AMP.The results suggested that large conformational change is induced by access of the transportable ATP and ADP, leading to the subsequent translocation, but not by that of the untransportable AMP and GTP.This is considered to be the initial recognition of ATP and ADP with the carrier.

从药物-受体相互作用过程的动态和三维结构变化的角度，我们开展了以下三个模型研究，以期了解这种相互作用及其在合理药物设计中的应用：1.一系列生物活性分子的新的定量构效关系(QSAR)分析；2.药物-受体相互作用的实验方法；我们开发了一种新的基于Voronoi多面体划分的三维QSAR程序。拟除虫菊酯类杀虫剂分子具有结构和构象多样性，很难通过常规的QSAR方法进行全面的了解。通过我们开发的QSAR和详尽的构象分析相结合的方法，我们已经成功地全面了解了拟除虫菊酯类化合物的QSAR。我们利用表面等离子体共振技术，利用光学生物传感器测量了刀豆蛋白A与各种碳水化合物之间的分子相互作用的定量大小，并构建了SAR模型。我们现在正准备在原子分辨水平上定量分析相互作用，参考α-甲基甘露糖与刀豆蛋白A之间络合物的X射线结晶学结果。作为含时动态药物-受体相互作用过程的模型，我们对ATP/ADP载体蛋白与ATP、ADP、GTP和AMP的相互作用进行了分子动力学计算。结果表明，可运输的ATP和ADP的进入引起了较大的构象变化，导致了随后的易位，而不是不能运输的AMP和GTP的结合，这被认为是ATP和ADP与载体的初步识别。