Please use this identifier to cite or link to this item:
https://hdl.handle.net/10316/25236
Title: | Is NMR Fragment Screening Fine-Tuned to Assess Druggability of Protein−Protein Interactions? | Authors: | Dias, David M. Van Molle, Inge Baud, Matthias G. J. Galdeano, Carles Geraldes, Carlos F. G. C. Ciulli, Alessio |
Keywords: | NMR fragment screening; protein−protein interactions; binding affinity; druggability | Issue Date: | 2014 | Publisher: | American Chemical Society | Project: | info:eu-repo/grantAgreement/EC/FP7/311460 | Serial title, monograph or event: | ACS Medicinal Chemistry Letters | Volume: | 5 | Issue: | 1 | 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 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. | URI: | https://hdl.handle.net/10316/25236 | ISSN: | 1948-5875 | DOI: | 10.1021/ml400296c | Rights: | openAccess |
Appears in Collections: | FCTUC Ciências da Vida - Artigos em Revistas Internacionais |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
ml400296c.pdf | 5.18 MB | Adobe PDF | View/Open |
SCOPUSTM
Citations
47
checked on Sep 30, 2024
WEB OF SCIENCETM
Citations
50
47
checked on Oct 2, 2024
Page view(s)
321
checked on Oct 8, 2024
Download(s)
265
checked on Oct 8, 2024
Google ScholarTM
Check
Altmetric
Altmetric
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.