ABSTRACT
The IL-2:IL-2R protein-protein interaction is of central importance to both healthy and diseased immune responses, and is one of the earliest examples of successful small-molecule inhibitor discovery against this target class. Drug-like inhibitors of IL-2 have been identified through a combination of fragment discovery, structure-based design, and medicinal chemistry; this discovery approach illustrates the importance of using a diverse range of complementary screening methods and analytical tools to achieve a comprehensive understanding of molecular recognition. The IL-2 story also provides insight into the dynamic nature of protein-protein interaction surfaces, their potential druggability, and the physical and chemical properties of effective small-molecule ligands. These lessons, from IL-2 and similar discovery programs, underscore an increasing awareness of the principles governing the development of drugs for protein-protein interactions.
