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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.

Citation

Yihao Li, Xiaoxuan Zhang, Jiali Xie, Dan Meng, Ming Liu, Yuxiang Chang, Guangrong Feng, Junhao Jiang, Ping Deng. Analyzing the Linker Structure of PROTACs throughout the Induction Process: Computational Insights. Journal of medicinal chemistry. 2025 Feb 13;68(3):3420-3432

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PMID: 39881546

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