Covalently-binding GPCR ligands: synthesis and biological investigation

G蛋白偶联受体（gpcr）是最重要的药物靶点。因此，超过30%的批准药物通过与gpcr结合发挥其生物活性。GPCR配体复合物的高分辨率x射线晶体结构极大地有助于理解其功能，并促进基于其结合袋而不是先导化合物的新型候选药物的基于结构的设计。开发共价结合受体配体，我们可以为GPCR的晶体结构做出贡献。在与斯坦福大学Brian Kobilka教授的合作中，我们打算开发新的共价配体，以解决亚型选择性的分子决定因素、Gq偶联受体的激活、功能选择性原理、受体二聚化和部分激动剂效应。此外，我们希望开发共价配体，利用基于纳米开关的技术作为发现新的筛选靶点的工具（与哈佛大学的Wesley Wong教授合作）。

G protein-coupled receptors (GPCRs) belong to the most important pharmaceutical targets. Thus, more than 30 % of the approved drugs exert their biological activity upon binding to GPCRs. High-resolution X-ray crystal structures of GPCR ligand complexes substantially contribute to the understanding of their function and facilitate a structure-based design of novel candidate drugs based on its binding pocket rather than lead compounds. Developing covalently binding receptor ligands, we could contribute to recent GPCR crystal structures. In continuation of our collaboration with Prof. Brian Kobilka (Stanford University), we intend to develop novel covalent ligands addressing molecular determinants of subtype selectivity, the activation of Gq coupled receptors, the principle of functional selectivity, receptor dimerization and partial agonist effects. Moreover, we wish to develop covalent ligands that may serve as tools to discover new screening hits by using nanoswitch based technology (collaboration with Prof. Wesley Wong, Harvard University).