Using a Fragment‐Based Approach To Target Protein–Protein Interactions

• DOI: 10.1002/cbic.201200521
• Publication Date: 2013-01-23T21:44:15Z
• Authors: Duncan E. Scott; Matthias T. Ehebauer; Tara Pukala; May Marsh; Tom L. Blundell; Ashok R. Venkitar...; Chris Abell; Marko Hyvönen
• Keywords: Isothermal Titration Calorimetry; Protein Engineering; Fragment (logic); Target protein

Abstract The ability to identify inhibitors of protein–protein interactions represents a major challenge in modern drug discovery and the development tools for chemical biology. In recent years, fragment‐based approaches have emerged as new methodology discovery; however, few examples small molecules that are active against chemotherapeutic targets been published. Herein, we describe approach targeting interaction between tumour suppressor BRCA2 recombination enzyme RAD51; it makes use screening pipeline biophysical techniques expect be more generally applicable similar targets. Disruption this vivo is hypothesised give rise cellular hypersensitivity radiation genotoxic drugs. We used protein engineering create monomeric form RAD51 by humanising thermostable archaeal orthologue, RadA, fragment screening. initial hits were thoroughly validated biophysically isothermal titration calorimetry (ITC) NMR observed X‐ray crystallography bind shallow surface pocket occupied native complex side chain phenylalanine from conserved FxxA motif found BRCA2. This first report fragments or any molecule binding at site.