NMR-Based Approaches for the Identification and Optimization of Inhibitors of Protein-Protein Interactions

The fundamental concepts of nuclear magnetic resonance (NMR)-based approaches to drug discovery and the use of these approaches to derive inhibitors of protein-protein interactions (PPIs) are reviewed. Most therapeutically relevant PPIs can be regarded as one protein functioning as a receptor and the other playing the role of its ligand. Hence, PPIs can often be targeted by peptides mimicking these secondary structure elements. The ligand in a PPI can be represented by peptides adopting a loop conformation. The binding pockets for these flexible loops are often also dynamic and thus are more likely to accommodate small molecules either from a fragment based approach or from a library of peptide mimetics. NMR spectroscopy allows one to study the interaction of proteins and compounds in solution using sensitive and robust assays that are less prone to artifacts. Protein-based NMR assays detect ligand binding by observing changes in NMR nuclei in the target protein in response to test ligands.