Protein–Protein Interactions (PPIs) constitute a promising class of targets for drug discovery. Inhibitors of these original interactions are certainly the next generation of highly innovative drugs that will reach the market in the next decade. However, the in silico design of such compounds still remains challenging. This review describes this particular protein-protein interaction chemical space and the main biophysical reasons that make them challenging targets for the drug discovery process. A state of the art of protein databases and servers dedicated to PPIs, their analysis and inhibition is also surveyed. It then presents some innovative methodologies that led to the development of new inhibitors. Finally, different families of protein-protein interactions for which an inhibitor is known are briefly introduced and potential tracks for the future are proposed such as a new classification based on protein-protein interfaces with known inhibitors into specific families, with a subsequent notion of focused databases dedicated to each specific class.
Keywords: protein-protein interactions, protein-protein interfaces, PPIs, 2P2I, drug design, inhibitor, small molecule, structural databases, druggable target.