儿茶素类天然生化调节剂-抗癌药物协同体系与蛋白质相互作用的量热学-谱学研究

项目名称： 儿茶素类天然生化调节剂-抗癌药物协同体系与蛋白质相互作用的量热学-谱学研究

项目编号： No.21473085

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 数理科学和化学

项目作者： 刘敏

作者单位： 聊城大学

项目金额： 86万元

中文摘要： 增强抗癌药物活性的同时降低其毒性，是癌症化疗领域的研究热点之一。生物医学研究证实天然生化调节剂可达到此目的，实现1+1>2。然而从分子水平上，揭示天然生化调节剂增强主抗癌药物疗效的机理，需获取其与抗癌药物及生物大分子相互作用的热力学信息。本项目拟采用等温滴定微量热技术，测定儿茶素类天然生化调节剂-抗癌药物协同物系与血浆蛋白的相互作用，获取结合位点数、结合平衡常数、焓变、熵变、Gibbs自由能变等热力学信息，探讨协同药物和蛋白质的分子结构及介质组成对此类相互作用体系热力学性质的影响规律。结合荧光光谱、圆二色谱、核磁共振波谱、动态光散射、分子模拟等手段，关联此类超分子体系的宏观热力学性质与微观作用模式，从微观结构诠释所得规律，阐明天然生化调节剂-抗癌药物发挥协同疗效的机理。研究结果将为开发新型生化调节剂提供新思路，为筛选出可供临床实验的新型药剂提供理论依据，具有重要理论意义和实际应用价值。

中文关键词： 微量热法；相互作用；抗癌药物；儿茶素类天然生化调节剂；蛋白质

英文摘要： One of the research focuses in the field of cancer chemotherapy is to enhance the anticancer activity and simultaneously reduce the toxicity of anticancer drugs. Biomedical researches have verified that natural biochemical modulators (NBMs) could accomplish this goal to achieve '1+1>2'. However, in order to investigate the mechanisms of NBMs enhancing curative effects of main anticancer drugs, it is necessary to obtain the thermodynamic information of the interactions of NBMs with the main drugs and biomacromolecules. This proposal will study the interactions of catechins NBM-anticancer drug synergistic medicines with plasma proteins using isothermal titration calorimetry (ITC). Thermodynamic parameters including binding sites number, binding equilibrium constants, changes in standard enthalpy, entropy and Gibbs free energy will be determined, and influencing rules of such important factors as molecular structures of the synergistic medicine and protein as well as compositions of the media on the thermodynamic properties will be investigated. The influencing rules will be explained with the help of fluorescence, CD, NMR, DLS and molecular simulation based on the correlation between the macroscopic thermodynamic properties and the microscopic interaction modes. The mechanisms of the synergistic therapy achieved by natural biochemical modulator-anticancer drug medicines will be clarified. The research results will provide new train of thought to develop novel biochemical modulators and a theoretical basis for their clinical application. Therefore, this study is of great theoretical and practical significance.

英文关键词： microcalorimetry;interaction;anticancer drug;catechins natural biochemical modulator;protein