Focusing on shared subpockets - new developments in fragment-based drug discovery.

INTRODUCTION: Protein-protein interactions (PPIs) are important targets for understanding fundamental biology and for the development of therapeutic agents. Based on different physicochemical properties, numerous pieces of software (e.g., POCKETQUERY, ANCHORQUERY and FTMap) have been reported to find pockets on protein surfaces and have applications in facilitating the design and discovery of small-molecular-weight compounds that bind to these pockets. AREAS COVERED: The authors discuss a pocket-centric method of analyzing PPI interfaces, which prioritize their pockets for small-molecule drug discovery and the importance of multicomponent reaction chemistry as starting points for undruggable targets. The authors also provide their perspectives on the field. EXPERT OPINION: Only the tight interplay of efficient computational methods capable of screening a large chemical space and fast synthetic chemistry will lead to progress in the rational design of PPI antagonists in the future. Early drug discovery platforms will also benefit from efficient rapid feedback loops from early clinical research back to molecular design and the medicinal chemistry bench.