Editorial [Hot Topic: Small Molecule Inhibition of Protein-Protein Interaction:An Emerging Paradigm in Drug Design (Guest Editor: Craig W. Lindsley)]

Protein-protein interactions (PPIs) are ubiquitous in biological systems, with essential functions in key of biological processes such as cell growth and differentiation, intracellular signaling and programmed cell death (apoptosis). Due to the pivotal role of PPIs, protein-protein interfaces have garnered attention as novel targets for therapeutic intervention in oncology, neuroscience and antiinfectives. However, the pharmaceutical industry has long regarded PPIs as intractable targets, which could only be disrupted by large macromolecules and peptides. Indeed, PPI targets are considerably more complex than classical enzyme targets, characterized by well-defined binding pockets and small molecule substrates, for a number of reasons. First, the natural protein ligand polypeptides of a PPI do not afford design opportunities for the development of small molecule leads and protein surfaces/residues which contribute to the binding interface are often unknown. Second, small molecule inhibitors appear to be at a disadvantage as the interacting protein-protein surfaces are large, featureless and often contain buried surfaces essential to the PPI. Finally, few small “drug like” leads have emerged from classical high-throughput screens aimed at identifying disruptors of PPIs, and alternative screening techniques are often required. Despite these significant challenges, progress has been made and small molecule disruptors of PPIs have been discovered. In large part, recent success in this field has been due to the pioneering work of Clarkson and Wells and the discovery of “hot spots”. Hot spots are small, high affinity regions at the protein-protein interface of many PPIs and can account for the majority (>80%) of the binding energy. As a result, disruptors of PPIs do not need to mimic the entire protein binding surface, but rather a smaller subset of key residues, suggesting small molecules can disrupt PPIs. There are now reports of a staggering diversity of small molecule chemotypes that disrupt PPIs and the concept of ‘privileged structures’, usually associated with GPCR ligands, can now be easily applied to small molecule PPIs. This issue contains a collection of reviews that describe state-of -the art screening techniques, medicinal chemistry strategies and case studies for various protein-protein targets. The authors have included the background biology needed to understand the target rationale and then have moved on to the screening paradigm, lead discovery and drug optimization stages as appropriate. The reader will find introductory reviews describing PPI chemotypes, screening techniques and system biology approaches followed by case studies on such important PPI targets as p53/HDM2, XIAP, Bcl-XL-BH3 and Nrf2-Keap1. I hope that this Issue serves to inspire and inform researchers interested in protein-protein interactions and accelerates scientific discovery in this arena.