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

点击翻译按钮获取中文摘要

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.