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

摘要

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.