调控蛋白磷酸化修饰的小分子设计策略  

Small-molecule drug design strategies for regulating protein phosphorylation modification

作　　者：杨文妍 王佳怡 林凤娇 王颗冉 吴煜卓 王兆成 尤启冬[1,2] 王磊 张秋月[1,2] YANG Wen-yan;WANG Jia-yi;LIN Feng-jiao;WANG Ke-ran;WU Yu-zhuo;WANG Zhao-cheng;YOU Qi-dong;WANG Lei;ZHANG Qiu-yue(Jiangsu Key Laboratory of Drug Design&Optimization,China Pharmaceutical University,Nanjing 210009,China;Department of Medicinal Chemistry,School of Pharmacy,China Pharmaceutical University,Nanjing 210009,China)

机构地区：[1]中国药科大学,江苏省药物分子设计与成药性优化重点实验室,江苏南京210009 [2]中国药科大学药学院药物化学系,江苏南京210009

出　　处：《药学学报》2024年第11期2912-2925,共14页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金面上项目(82173741,82003582,81930100);国家自然科学青年基金项目(82304309);江苏省自然科学青年基金项目(BK20231014);中国博士后科学基金项目(2022M723512);江苏省“卓博计划”(2023ZB429);中央高校基本科研业务费专项资金资助项目(2632023GR13);大学生创新创业训练计划项目成果(3312300067,202410316058Y)。

摘　　要：蛋白磷酸化修饰是机体内的一种调节机制,与蛋白生物学功能紧密相关,在细胞的生理活动中发挥着关键作用。其中,蛋白激酶负责催化蛋白的磷酸化过程,磷酸酶负责将磷酸化修饰的蛋白去磷酸化,实现对蛋白动态可逆的磷酸化修饰。蛋白的磷酸化水平异常往往会导致许多疾病的发生,包括恶性肿瘤、神经退行性疾病、各类慢性疾病等。因此,合理设计小分子调控蛋白磷酸化修饰是一种重要的疾病治疗手段。基于蛋白磷酸化调控的机制,小分子药物设计策略可以分为三种,蛋白激酶调控剂、磷酸酶调控剂以及基于诱导拉近机制的双功能分子。本文重点阐述这三种靶向蛋白磷酸化调控的小分子设计策略,包括分子设计思路、研究进展和当前存在问题,并对靶向蛋白磷酸化修饰的小分子调控剂进行展望。Protein phosphorylation modification is an important mechanism of physiological regulation that is closely related to protein biological functions.In particular,protein kinases are responsible for catalyzing the phosphorylation process of proteins,and phosphatases are responsible for catalyzing the dephosphorylation process of phosphorylation-modified proteins,which together mediate the achievement of dynamic and reversible phosphorylation modifications of proteins.Abnormal phosphorylation levels of proteins contribute to the development of many diseases,such as cancer,neurodegenerative diseases,and chronic diseases.Therefore,rational design of small molecules to regulate protein phosphorylation is an important approach for disease treatment.Based on the mechanism of protein phosphorylation regulation,small molecule drug design strategies can be classified into three types,protein kinase modulators,phosphatase modulators,and bifunctional molecules with proximity-mediated mechanism.This review emphasizes the above three small molecule design strategies for targeting protein phosphorylation regulation,including molecular design ideas,research progress and current challenges,and provides an outlook on small molecule modulators targeting protein phosphorylation modification.

关 键 词：磷酸化调控 小分子设计 激酶 磷酸酶 双功能分子 

分 类 号：R914[医药卫生—药物化学]