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

David M. Dias, Inge Van Molle, Matthias G. J. Baud, Carles Galdeano, Carlos F. G. C. Geraldes, Alessio Ciulli

    Research output: Contribution to journalLetter

    26 Citations (Scopus)

    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-1a). 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.
    Original languageEnglish
    Pages (from-to)23-28
    Number of pages6
    JournalACS Medicinal Chemistry Letters
    Volume5
    Issue number1
    DOIs
    Publication statusPublished - 9 Jan 2014

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    Screening
    Nuclear magnetic resonance
    Proteins
    Alpha Subunit Hypoxia-Inducible Factor 1
    Ligands
    Epitope Mapping
    Calorimetry
    X Ray Crystallography
    Protein Subunits
    X ray crystallography
    Titration
    Epitopes
    Modulation
    Molecules

    Cite this

    Dias, David M. ; Van Molle, Inge ; Baud, Matthias G. J. ; Galdeano, Carles ; Geraldes, Carlos F. G. C. ; Ciulli, Alessio. / Is NMR fragment screening fine-tuned to assess druggability of protein-protein interactions?. In: ACS Medicinal Chemistry Letters. 2014 ; Vol. 5, No. 1. pp. 23-28.
    @article{eebecb410d8c4793a39902401f7dfb68,
    title = "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-1a). 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.",
    author = "Dias, {David M.} and {Van Molle}, Inge and Baud, {Matthias G. J.} and Carles Galdeano and Geraldes, {Carlos F. G. C.} and Alessio Ciulli",
    year = "2014",
    month = "1",
    day = "9",
    doi = "10.1021/ml400296c",
    language = "English",
    volume = "5",
    pages = "23--28",
    journal = "ACS Medicinal Chemistry Letters",
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    Is NMR fragment screening fine-tuned to assess druggability of protein-protein interactions? / Dias, David M.; Van Molle, Inge; Baud, Matthias G. J.; Galdeano, Carles; Geraldes, Carlos F. G. C.; Ciulli, Alessio.

    In: ACS Medicinal Chemistry Letters, Vol. 5, No. 1, 09.01.2014, p. 23-28.

    Research output: Contribution to journalLetter

    TY - JOUR

    T1 - Is NMR fragment screening fine-tuned to assess druggability of protein-protein interactions?

    AU - Dias, David M.

    AU - Van Molle, Inge

    AU - Baud, Matthias G. J.

    AU - Galdeano, Carles

    AU - Geraldes, Carlos F. G. C.

    AU - Ciulli, Alessio

    PY - 2014/1/9

    Y1 - 2014/1/9

    N2 - 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-1a). 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.

    AB - 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-1a). 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.

    U2 - 10.1021/ml400296c

    DO - 10.1021/ml400296c

    M3 - Letter

    VL - 5

    SP - 23

    EP - 28

    JO - ACS Medicinal Chemistry Letters

    JF - ACS Medicinal Chemistry Letters

    SN - 1948-5875

    IS - 1

    ER -