DRUG MOLECULAR DESIGN BASED ON THE FUNCTIONAL ANALYSIS OF DRUG TRANSPORTERS

ATP结合盒（ABC）转运蛋白是药物及其代谢产物转运的重要机制。ABC转运蛋白的底物特异性筛选对于实现合理的药物分子设计具有重要意义。在本项目中，我们克隆了人类新型ABC转运蛋白，如ABCC 11，ABCC 12和ABCC 13，并开发了高速功能筛选系统。利用化学片段化编码，我们建立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。ABCG 2的底物特异性的分析使我们发现了新的喜树碱（CPT）为基础的药物，可能会规避人类癌症的耐药性。基于我们的数据，它强烈建议，氢键的形成是至关重要的参与底物识别和/或运输过程的ABCG 2。此外，我们进行了基于结构的分子设计，以发现一个高选择性的丝氨酸/苏氨酸蛋白磷酸酶2B（PP 2B/calcineurin）的催化定点抑制剂。由此产生的基于藜芦素的抑制剂对PP 2B非常有效且特异性，而不抑制PP 1或PP 2A。据我们所知，这是PP 2B的第一个高选择性催化位点定向抑制剂。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，我们还成功地合成了有效抑制癌细胞侵袭的PKC抑制剂。

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.