Protein-Protein Interactions in Drug Discovery

Although the regulation of cellular processes is mediated to a large extent by posttranslational modification of proteins, the target specificity of enzymatic, e.g. protein kinase and phosphatase, activities derives in large part from protein-protein interactions (PPIs) rather than enzyme substrate specificity. Similarly, signal transduction through interaction of biological effectors such as hormones and cytokines with their receptors is mediated by PPIs. For this reason PPIs represent attractive targets for modern mechanism based drug design. PPIs have been more difficult to modulate pharmacologically with drug-like small molecules than catalytic sites, however. The reasons for this apparent lack of success with PPI inhibitors are discussed here and new insights into the requirements for effective PPI modulation from both the ligand and receptor viewpoints are summarised. In particular, the emerging concept of protein plasticity and its implications for drug discovery and design are introduced. Recent breakthroughs with drug-like small molecules targeting PPIs are presented as a series of case studies in order to illustrate modern concepts and peptidomimetic techniques that will hopefully result in the development of a new generation of disease mechanism based PPI modulator drugs.