EP3是体内重要的前列腺素E2（PGE2）受体蛋白，现代生物医学研究证实它与人类心脑血管疾病及恶性肿瘤的形成有关。其亚型（isoforms）的多样性以及它们对生理体系调节作用的复杂性大大阻碍了相关药物研发的进程。本课题将结合我们前期研究成果，首先利用基因工程的手段建立EP3主要亚型蛋白的表达体系；在此基础上应用STD-NMR辅助片段分子活性分析，计算机辅助设计和药物化学等方法在靶点蛋白水平上阐明不同EP3亚型与配体间亲和机制，确定配体分子结构的活性部位；在化学生物学研究的基础上理解EP3不同亚型及其选择性调节剂的抗凝血机制，总结EP3亚型调节剂的构效关系；最后通过细胞生物学实验手段了解不同亚型及其调节剂与肿瘤细胞生长的关联性，从靶点蛋白的层面上找出癌变毒副作用的成因。综合上述研究结果推出高效低毒的EP3调节剂的理想分子结构模型，为相关药物研究奠定理论基础。

Physiologically the EP3 isoforms are important in a number of functions including the platelet aggregation process and several carcinogenic cell developments...In this study, we will first create the desired protein expressing systems of the different EP3 isoforms employing genetic engineer method, design and prepare the desired synthetic ligands/functional molecular fragments. The proteins and ligands will be subjected to the STD-NMR assistant fragment affinity analysis, computer modeling and bioassay (binding & functional assay) to determine the binding properties between EP3 isoforms and their related synthetic ligands. The above data will be used to explain the binding mechanism of the selected ligands on the EP3 isoforms. At the same time, we will collect enough information about the structure's active positions of several series of modulatory molecular and then summarize their SAR relationship. The antiplatelet aggregation mechanism of the EP3 isoforms and selected modulators will be clarified with the assistantance of chemi-biological experimental method and then the isoforms and their carefully selected modulators will be subjected to cell biological experiments to determine their roles in the related carcinogenic cell development. Therefore, the cause of the related carcinogenic toxicity of the EP3 modulators will be uncovered from the biological targets (EP3 isoforms) point of view. ..Finally the ideal antiplatelet modular's molecular model of the different isoforms with high efficance and safety will be proposed to help the related EP3 based drug discovery in the future.