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）转运蛋白代表了药物运输及其代谢产物的重要机制。 ABC转运蛋白的底物特异性筛选是实现合理药物分子设计的目标引起的。在这个项目中，我们克隆了人类的新型ABC转运蛋白，例如ABCC11，ABCC12和ABCC13，并开发了高速功能筛选系统。通过使用化学片段化代码，我们创建了一种新的定量结构活性关系（QSAR）分析方法来研究ABC转运蛋白的底物特异性。对ABCG2的底物特异性的分析使我们发现了新的camptothecin（CPT）的药物，这些药物可能避免了对人类癌症的抗药性。根据我们的数据，强烈建议形成氢键参与ABCG2的底物识别和/或运输过程。此外，我们进行了基于结构的分子设计，以发现Ser/Thr蛋白磷酸酶2B（PP2B/钙调蛋白）的高度选择性催化位点定向的抑制剂。因此创建的基于cantharidin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，这是第一个高度选择性的催化位点导向PP2B的抑制剂。此外，我们设计了与TPA一样有效的新型蛋白激酶C（PKC）配体。通过结构修饰，我们还成功地合成了有效抑制癌细胞侵袭的PKC抑制剂。