DRUG MOLECULAR DESIGN BASED ON THE FUNCTIONAL ANALYSIS OF DRUG TRANSPORTERS

基于药物转运蛋白功能分析的药物分子设计

基本信息

批准号：
14370754
负责人：
ISHIKAWA Toshihisa
金额：
$ 8.83万
依托单位：
Tokyo Institute of Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

The ATP-binding cassette(ABC) transporters represent an important mechanism in transport of drugs and their metabolites. Substrate specificity screening of ABC transporters is of great interest to achieve a goal of rational drug molecular design. In this project, we have cloned human novel ABC transporters, such as ABCC11, ABCC12, and ABCC13, and also developed high-speed functional screening systems. By using the Chemical Fragmentation Codes, we have created a new quantitative structure-activity relationship(QSAR) analysis method to study the substrate specificity of ABC transporters. Analysis of the substrate specificity of ABCG2 led us to discovery of new camptothecin (CPT)-based drugs that may circumvent drug-resistance of human cancer. Based on our data, it is strongly suggested that hydrogen bond formation is critically involved in substrate recognition and/or transport processes of ABCG2. Furthermore, we performed structure-based molecular design to discover a highly selective catalytic site-directed inhibitor of Ser/Thr protein phosphatase 2B (PP2B/calcineurin). The cantharidin-based inhibitor, thus created, is very potent and specific to PP2B without inhibiting PP1 or PP2A. To our knowledge, this is the first highly selective catalytic-site-directed inhibitor of PP2B. In addition, we have designed novel protein kinase C(PKC) ligands that are as potent as TPA. By structural modifications, we have also succeeded in synthesizing PKC inhibitors that effectively inhibit the invasion of cancer cells.

ATP结合盒（ABC）转运蛋白是药物及其代谢物转运的重要机制。 ABC转运蛋白的底物特异性筛选对于实现合理药物分子设计的目标具有重要意义。在这个项目中，我们克隆了人类新型ABC转运蛋白，如ABCC11、ABCC12和ABCC13，并开发了高速功能筛选系统。通过使用化学碎片代码，我们创建了一种新的定量构效关系（QSAR）分析方法来研究ABC转运蛋白的底物特异性。对 ABCG2 底物特异性的分析使我们发现了新的基于喜树碱 (CPT) 的药物，可以规避人类癌症的耐药性。根据我们的数据，强烈表明氢键的形成在 ABCG2 的底物识别和/或运输过程中至关重要。此外，我们进行了基于结构的分子设计，发现了一种高选择性催化定点抑制剂 Ser/Thr 蛋白磷酸酶 2B (PP2B/钙调神经磷酸酶)。由此产生的基于斑蝥素的抑制剂非常有效并且对 PP2B 具有特异性，而不抑制 PP1 或 PP2A。据我们所知，这是第一个高选择性的 PP2B 催化定点抑制剂。此外，我们还设计了与 TPA 一样有效的新型蛋白激酶 C (PKC) 配体。通过结构修饰，我们还成功合成了有效抑制癌细胞侵袭的PKC抑制剂。