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Letter. Is NMR fragment screening fine-tuned to assess druggability of protein–protein interactions?

Letter. Is NMR fragment screening fine-tuned to assess druggability of protein–protein interactions?
Letter. Is NMR fragment screening fine-tuned to assess druggability of protein–protein interactions?
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.
1948-5875
23-28
Dias, David M.
a949222a-b965-4946-b380-b29a3eeb2eb7
Van Molle, Inge
dd91aba7-8b90-42a7-958b-5b87b8a41c44
Baud, Matthias
8752d519-3d33-43b6-9a77-ab731d410c2e
Galdeano, Carles
963c82d7-26a8-4e94-8623-e854e065c997
Geraldes, Carlos F.G.C.
c109bc54-a4f6-4d80-8bc8-bf30f8d3fce1
Ciulli, Alessio
6a734270-055b-47ed-b97d-51cff3fb50f1
Dias, David M.
a949222a-b965-4946-b380-b29a3eeb2eb7
Van Molle, Inge
dd91aba7-8b90-42a7-958b-5b87b8a41c44
Baud, Matthias
8752d519-3d33-43b6-9a77-ab731d410c2e
Galdeano, Carles
963c82d7-26a8-4e94-8623-e854e065c997
Geraldes, Carlos F.G.C.
c109bc54-a4f6-4d80-8bc8-bf30f8d3fce1
Ciulli, Alessio
6a734270-055b-47ed-b97d-51cff3fb50f1

Dias, David M., Van Molle, Inge, Baud, Matthias, Galdeano, Carles, Geraldes, Carlos F.G.C. and Ciulli, Alessio (2014) Letter. Is NMR fragment screening fine-tuned to assess druggability of protein–protein interactions? ACS Medicinal Chemistry Letters, 5 (1), 23-28. (doi:10.1021/ml400296c). (PMID:24436777)

Record type: Article

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.

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Accepted/In Press date: 2 November 2013
e-pub ahead of print date: 3 November 2013
Published date: 9 January 2014

Identifiers

Local EPrints ID: 400506
URI: http://eprints.soton.ac.uk/id/eprint/400506
ISSN: 1948-5875
PURE UUID: 3582b92d-6e9e-4b02-b43d-7915eed9be4b
ORCID for Matthias Baud: ORCID iD orcid.org/0000-0003-3714-4350

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Date deposited: 16 Sep 2016 15:42
Last modified: 12 Nov 2019 01:33

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