基于片段的P2Y14受体拮抗剂的设计、合成和抗炎活性研究

嘌呤受体P2Y14R是一个G蛋白偶联受体，在炎症的发生过程中起到关键作用，开发P2Y14R的拮抗剂可以达到治疗炎症等相关疾病的目的。目前发现的P2Y14R拮抗剂均为通过高通量筛选和局部的结构改造获得，结构类型非常有限。由于目前P2Y14R三维晶体结构尚不知晓，通常采用P2Y12R进行同源模建的晶体结构来进行结合模式的模拟，然而，进一步的结构修饰和优化缺乏可靠的指导。本课题在前期工作基础上，采用基于片段的药物设计思路，通过对与受体中不同区域结合的片段进行探索和优化，寻找到适合不同结合区域的优势片段，通过对各优势片段进行整合、组装，丰富P2Y14R拮抗剂的结构类型。本项目的成功实施，可发现具有全新结构的高活性、选择性且具有较好成药性的P2Y14R拮抗剂，并为进一步的结构优化提供可靠的指导信息。

The P2Y14 receptor (P2Y14R) belongs to the G protein-coupled receptors (GPCRs) which acts as a key role in mediating inflammatory activity. Discovery and development of P2Y14R antagonists can be used for the treatment of inflammatory diseases. Up to date, only very limited classes of antagonists have been identified through high-throughput screening followed by special structure modification. As the three-dimensional structure of the P2Y14R has not yet been elucidated, X-ray crystallographic structures of the closely related P2Y12R have been used to predict the binding mode of various ligands. However, the effective and reliable direction for further modification and optimization is uncertain. Based on our previous research, fragment-based drug design strategy is applied in this project. Fragments which are critical to the binding of these compounds to P2Y14R can be found and optimized. Through reorganization and assembling of these fragments, we can identify a series of novel P2Y14R antagonists. The structural diversity will be extended which can also provide reliable information for further structural optimization. Successfully carrying out, our project will lead to the discovery of novel potent, selective P2Y14R antagonists with good druggability.