化学
连接器
过程(计算)
计算生物学
生化工程
计算机科学
生物
操作系统
工程类
作者
Yihao Li,Xiaoxuan Zhang,Jiali Xie,Dan Meng,Ming Liu,Y N Chang,Guangrong Feng,Junhao Jiang,Ping Deng
标识
DOI:10.1021/acs.jmedchem.4c02637
摘要
Linker structures are a crucial component of proteolysis-targeting chimeras (PROTACs) and have traditionally been designed based on empirical methods, which presents significant challenges in the development of PROTACs. Current optimization strategies typically focus on reducing the number of rotatable bonds in the linker to limit conformational freedom. However, this approach overlooks the complexity of the target protein degradation process. Retrospective analyses suggest that merely adjusting the rotatable bonds in the linker is insufficient to control the conformational freedom of the PROTACs, indicating the need for new optimization strategies. By integration of computational methods such as molecular dynamics simulations, this study investigates the role of the linker throughout the induction process, particularly its impact on the formation and stability of the ternary complex. This approach offers potential for overcoming the limitations of traditional strategies, reducing reliance on empirical methods, and enhancing the overall efficiency and effectiveness of PROTAC design.
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