Small-molecule inhibitors of protein-protein interactions: progressing towards the dream

Key Points Protein–protein interactions represent a large and important class of targets for human therapeutics. However, developing small-molecule antagonists of protein–protein interactions is challenging, owing to issues such as the general lack of small-molecule starting points for drug design, the typical flatness of the interface, the difficulty of distinguishing real from artefactual binding, and the size and character of typical small-molecule libraries. This article uses examples to describe general strategies in the development of small molecule antagonists of protein–protein interactions. Two types of antagonists are described: those that bind directly to the 'hot spot'of a protein–protein interface — a region that has a major contribution to high-affinity binding — and those that bind at allosteric sites distal from the protein–protein interface. Finally, characteristics of programmes that have successfully identified small-molecule antagonists of protein–protein interactions are discussed. A high degree of validation is recommended for antagonists of protein–protein interactions owing to the nature of these targets, and a series of steps for validating and characterizing a new series of antagonists are presented. Protein–protein interactions have a key role in most biological processes, and offer attractive opportunities for therapeutic intervention. Developing small molecules that modulate protein–protein interactions is difficult, owing to issues such as the lack of well-defined binding pockets. Nevertheless, there has been important progress in this endeavour in recent years. Here, we use illustrative examples to discuss general strategies for addressing the challenges inherent in the discovery and characterization of small-molecule inhibitors of protein–protein interactions.