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

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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: ABT-737; Alpha-helices; BH3-helix; Bcl-2; Bcl-2 family; Bcl-XL; DNA replication; HCS assays; HDM2; HematideTM; IC50 9 nM; Janus kinases 2; Ligand-based drug discovery; Multiple Protein Structure; Myc-Max dimer; Normal Mode Analyses; Nuclear magnetic resonance (NMR)spectroscopy; PDZ; PTB; Protein-protein interactions; SH2; SH3; SMAC; Thr803; Trp800; Val807; WW; X-ray crystallography (XRC); allosteric binding sites; anti-apoptotic members; biochemical assay; c-Myc-Max heterodimer; cIAP-1; cIAP-2; calmodulin; cancer; computer-aided drug discovery; drug discovery; erythropoietin; fragment-based drug discovery; hematopoietic growth hormone; high-throughput screening; hotspots; human serum albumin; isothermal titration calorimetry; ligandbased pharmacophore; ligands; low-affinity binders; lung cancer; lymphomas; mass spectrometry; p53; p53-MDM2/HDM2; peptide based drug discovery; protein secondary structure mimetics; receptor-based pharmacophore; sheets; signal transduction; smMLCK; small molecules; small-molecule modulators; surface plasmon resonance (SPR); terephthalamide scaffold; tethering; tri-substituted imidazole backbone; tumor suppressor protein; tumorigenesis; turn mimetic scaffolds; turns; undruggable

Document Type: Research Article

Publication date: February 1, 2011

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