Is NMR Fragment Screening Fine-Tuned to Assess Druggability of Protein-Protein Interactions?

ABSTRACT: Modulation of protein-protein interactions (PPIs) with small molecules has been hampered by a lack of lucid methods capable of reliably identifying high-quality hits. In fragment screening, the low ligand efficiencies associated with PPI target sites pose significant challenges to fragment binding detection. Here, we investigate the requirements for ligand-based NMR techniques to detect rule-of-three compliant fragments that form part of known high-affinity inhibitors of the PPI between the von Hippel-Lindau protein and the alpha subunit of hypoxia-inducible factor 1 (pVHL:HIF-1α). Careful triaging allowed rescuing weak but specific binding of fragments that would otherwise escape detection at this PPI. Further structural information provided by saturation transfer difference (STD) group e

SUBMITTER: Dias DM 

PROVIDER: S-EPMC3891296 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature