The ternary complex structure as a foundation for structure-guided molecular glue design.

Abstract

Molecular glues are opening up new therapeutic areas by turning previously undruggable and intractable proteins into tractable targets through the formation or stabilisation of a ternary complex between two proteins. The present review focuses on how such structures are obtained and leveraged to guide rational design. Ternary complexes can be classified by protein-protein interface architecture and degree of topological constraint, informing the design process towards a given biological outcome. As with conventional small-molecule drug discovery, structural information provides invaluable insights for rational optimisation of glues, but solving a ternary complex structure remains a significant challenge owing to the underlying three-body equilibrium. Biophysical characterisation of cooperativity and ternary complex half-life not only provides optimisation parameters but also provides a means for prioritising the most promising glues for ternary structural studies by X-ray crystallography or cryogenic electron microscopy. Once solved, a ternary structure enables conventional structure-based design, such as scaffold hopping and surface decoration, and increasingly informs computational methods, though these remain most powerful when grounded in experimental validation. Ternary complex structures for canonical glue systems are now available in relative abundance, providing a foundation for both empirical and computational design; expanding this coverage beyond well-studied glue receptors and binding partners will test how broadly these principles generalise.