Analyzing the Linker Structure of PROTACs throughout the Induction Process: Computational Insights

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.