Discovery of Modulators of Protein-Protein Interactions: Current Approaches and Limitations

Protein – protein interactions are involved in most of the essential processes that occur in living organisms from cell motility to DNA replication, which makes them interesting targets for drug discovery. However, due to the lack of deep pockets, and the large contact surfaces involved in these interactions, they are considered challenging targets and have been often times dismissed as “undruggable”. Nonetheless, significant efforts in pharmaceutical and academic laboratories have been devoted to finding ways to exploit protein-protein interactions as drug targets. This article provides an overview of the principles underlying the main general strategies for discovering small-molecule modulators of protein-protein interactions, namely: high-throughput screening, fragment-based drug discovery, peptide-based drug discovery, protein secondary structure mimetics, and computer-aided drug discovery. In addition, examples of successful discovery of modulators of protein-protein interactions are discussed for each of those strategies. Keywords: Protein-protein interactions, small molecules, high-throughput screening, fragment-based drug discovery, peptide based drug discovery, protein secondary structure mimetics, computer-aided drug discovery, DNA replication, drug discovery, cancer, hotspots, small-molecule modulators, undruggable, ligands, allosteric binding sites, HCS assays, tumor suppressor protein, p53, HDM2, p53-MDM2/HDM2, Nuclear magnetic resonance (NMR)spectroscopy, X-ray crystallography (XRC), surface plasmon resonance (SPR), mass spectrometry, isothermal titration calorimetry, low-affinity binders, biochemical assay, tethering, anti-apoptotic members, Bcl-2 family, Bcl-XL, Bcl-2, tumorigenesis, BH3-helix, human serum albumin, ABT-737, lung cancer, SMAC, cIAP-1, cIAP-2, lymphomas, signal transduction, PDZ, SH2, SH3, PTB, WW, hematopoietic growth hormone, erythropoietin, Janus kinases 2, HematideTM, Alpha-helices, sheets, turns, turn mimetic scaffolds, smMLCK, calmodulin, Trp800, Thr803, Val807, IC50 9 nM, terephthalamide scaffold, tri-substituted imidazole backbone, Myc-Max dimer, Multiple Protein Structure, Normal Mode Analyses, Ligand-based drug discovery, receptor-based pharmacophore, ligandbased pharmacophore, c-Myc-Max heterodimer