孤儿G蛋白偶联受体GPR52负向别构调控剂设计和机制研究

G蛋白偶联受体（GPCR）是一大类位于细胞膜的蛋白质受体，在人体中有800多个成员，是最大的一类药物靶标。目前GPCR中有100多个孤儿受体，即内源性配体尚未确定。许多孤儿受体具有重要功能，但如何参与生理过程仍不清楚，是目前GPCR研究的难点之一。GPR52是一个近年来受到重视的孤儿受体，在中枢神经系统中具有重要的调控作用，抑制其信号通路具有治疗亨廷顿病的前景，但目前其拮抗剂报道较少。2020年，GPR52的高分辨率结构得到解析，为基于结构的药物提供了基础。本项目拟采用计算生物学方法结合实验手段，1) 针对于胞内界面进行负向别构筛选；2) 对发现的活性分子进行结构改造和机制研究。项目的开展，将为研究孤儿受体的信号通路转导提供理论基础，并为亨廷顿病药物的研发提供新的起点。

G protein-coupled receptors (GPCRs) belong to a large family of protein receptors located on cell membrane. There are over 800 GPCRs in human body, forming the largest family of drug target. Currently, for more than 100 GPCRs, the endogenous ligands are not identified, and they are called orphan GPCRs. Many orphan GPCRs play key roles in human body, but how they participate in physiological processes is unknown, and this is a difficult point in study of GPCRs. GPR52 is an orphan GPCR received much attention in recent years for its important regulatory function in central nervous system. Inhibiting GPR52 signaling pathway might be a therapy for Huntingtin's disease, however there are very few reports of GPR52 antagonists. In 2020, high-resolution structures of GPR52 were reported, providing basis for structure-based drug design. In this project we planned to use computational biology methods combining experimental techniques, 1) To discover negative allosteric modulators binding at GPR52 cytoplasmic surface; 2) To increase the activity of the negative allosteric modulators through structural optimization and to study their mechanisms. Development of this project will bring insight for the signal transduction of orphan receptors, and provide new starting points for drugs discovery against Huntingtin's disease.