Leveraging Structural and Computational Biology for Molecular Glue Discovery

Abstract

The discovery of molecular glues has made significant strides, unlocking new avenues for targeted protein degradation as a therapeutic strategy, thereby expanding the scope of drug discovery into territories previously considered undruggable. Pioneering molecules like thalidomide and its derivatives have paved the way for the development of small molecules that can induce specific protein degradation by hijacking the cellular ubiquitin–proteasome system. Recent advancements have focused on expanding the range of E3 ligases and target proteins that can be modulated by molecular glues. Structural elucidation of E3 ligase in complex with molecular glue and the target of interest, combined with computational modeling, facilitates the understanding of the underlying mechanisms of how molecular glues induce targeted degradation. By leveraging these tools, the next generation of molecular glues are expected to offer unprecedented opportunities for combating a wide range of diseases, including cancer, autoimmune disorders, and neurodegenerative conditions.