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

DOI: 10.1021/ml400296c DOI Help
PMID: 24436777 PMID Help

Authors: David M. Dias (University of Cambridge) , Inge Van Molle (University of Cambridge) , Matthias G. J. Baud (University of Cambridge) , Carles Galdeano (University of Cambridge) , Carlos F. G. C. Geraldes (University of Coimbra) , Alessio Ciulli (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 5 (1)

State: Published (Approved)
Published: November 2013

Open Access Open Access

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-1?). 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 epitope mapping, protein-based NMR, competitive isothermal titration calorimetry (ITC), and X-ray crystallography confirmed the binding mode of the rescued fragments. Our findings have important implications for PPI druggability assessment by fragment screening as they reveal an accessible threshold for fragment detection and validation.

Journal Keywords: Nmr Fragment Screening; Protein−Protein Interactions; Binding Affinity; Druggability

Subject Areas: Biology and Bio-materials, Technique Development

Instruments: I02-Macromolecular Crystallography