生物信息学及分子模拟在蛋白质降解靶向嵌合体(PROTAC)中的研究  

Research on bioinformatics and molecular simulation in proteolysis targeting chimeras(PROTAC)

作　　者：朱婕[1] 聂锦宜 刘小益 梁中洁[1,2] ZHU Jie;NIE Jin-yi;LIU Xiao-yi;LIANG Zhong-jie(Suzhou Medical College of Soochow University,Suzhou 215123,China;Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development,Suzhou 215123,China)

机构地区：[1]苏州大学苏州医学院,江苏苏州215123 [2]江苏省精准诊疗药物创制工程研究中心,江苏苏州215123

出　　处：《药学学报》2024年第6期1546-1561,共16页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金项目(22377089);江苏省高等学校重点学科建设项目(PAPD);大学生创新创业训练计划项目(202210285179Y).

摘　　要：蛋白质降解靶向嵌合体(proteolysis targeting chimera,PROTAC)是一种利用泛素−蛋白酶体系统(ubiquitin proteasome system,UPS)对靶标蛋白进行降解的药物开发技术。与传统小分子药物通过“占位驱动”作用模式调控蛋白质活性的方式不同,PROTAC通过形成稳定的靶蛋白-PROTAC-E3泛素连接酶三元复合物,并利用泛素−蛋白酶体系统降解靶标蛋白而发挥作用。然而,目前只有少数E3泛素连接酶被用到PROTAC分子设计中,PROTAC可靶向的靶标蛋白空间也有待进一步拓展;另一方面,靶蛋白-PROTAC-E3泛素连接酶的三元复合物晶体结构解析难度较大,计算模拟方法为构建三元复合物模型提供了有效的工具。基于此,本文介绍了生物信息学在拓展E3泛素连接酶及扩大靶标蛋白空间方面的研究进展,总结了计算模拟在PROTAC三元复合物结构模拟中的方法研究,并探讨了PROTAC技术的发展趋势。Proteolysis targeting chimera(PROTAC)is a drug discovery strategy using ubiquitin proteasome system(UPS)to degrade the target protein.Unlike traditional small molecule drugs utilizing occupancy-driven pharmacology as the mode of action(MOA)to regulate protein activity,PROTACs function through forming stable target protein-PROTAC-E3 ubiquitin ligase ternary complex and use ubiquitin proteasome system to degrade the target protein.However,only a few E3 ubiquitin ligases have been used in PROTAC drug design now,and the space of target proteins that PROTAC can target needs to be further expanded.On the other hand,the complicated system of ternary crystal structures is difficult to capture and identify,computational simulation provides modeling of PROTAC-mediated ternary complex formation with effective approaches.In view of this,this review describes the recent progress of bioinformatics on expanding the landscape of E3 ubiquitin ligases and target proteins,and summarizes the methods of computation simulation in modeling PROTAC ternary complex.Finally,the trend of development about PROTAC is prospected.

关 键 词：蛋白质降解靶向嵌合体 E3泛素连接酶 靶标空间 三元复合物结构模拟 蛋白质翻译后修饰 异双功能分子 

分 类 号：R914[医药卫生—药物化学]