The “three body solution”: Structural insights into molecular glues

Abstract

Molecular glues are small molecules that nucleate novel or stabilize natural, protein–protein interactions resulting in a ternary complex. Their success in targeting difficult to drug proteins of interest has led to ever-increasing interest in their use as therapeutics and research tools. While molecular glues and their targets vary in structure, inspection of diverse ternary complexes reveals commonalities. Whether of high or low molecular weight, molecular glues are often rigid and form direct hydrophobic interactions with their target protein. There is growing evidence that these hotspots can accommodate multiple ternary complex binding modes and enable targeting of traditionally undruggable targets. Advances in screening from the molecular glue degrader literature and insights in structure-based drug design, especially from the non-degrading tri-complex work, are likely intersectional.