Discovery of Β2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor

Tonia Aristotelous, Seungkirl Ahn, Arun K. Shukla, Sylwia Gawron, Maria F. Sassano, Alem W. Kahsai, Laura M. Wingler, Xiao Zhu, Prachi Tripathi-Shukla, Xi-Ping Huang, Jennifer Riley, Jeremy Besnard, Kevin D. Read, Bryan L. Roth, Ian H. Gilbert, Andrew L. Hopkins (Lead / Corresponding author), Robert J. Lefkowitz (Lead / Corresponding author), Iva Navratilova (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    41 Citations (Scopus)

    Abstract

    G-protein coupled receptors (GPCRs) are the primary target class of currently marketed drugs, accounting for about a quarter of all drug targets of approved medicines. However, almost all the screening efforts for novel ligand discovery rely exclusively on cellular systems overexpressing the receptors. An alternative ligand discovery strategy is a fragment-based drug discovery, where low molecular weight compounds, known as fragments, are screened as initial starting points for optimization. However, the screening of fragment libraries usually employs biophysical screening methods, and as such, it has not been routinely applied to membrane proteins. We present here a surface plasmon resonance biosensor approach that enables, cell-free, label-free, fragment screening that directly measures fragment interactions with wild-type GPCRs. We exemplify the method by the discovery of novel, selective, high affinity antagonists of human β2 adrenoceptor.
    Original languageEnglish
    Pages (from-to)1005-1010
    Number of pages6
    JournalACS Medicinal Chemistry Letters
    Volume4
    Issue number10
    DOIs
    Publication statusPublished - 2013

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    Biosensing Techniques
    G-Protein-Coupled Receptors
    Biosensors
    Adrenergic Receptors
    Screening
    Ligands
    Surface Plasmon Resonance
    Drug Discovery
    Pharmaceutical Preparations
    Membrane Proteins
    Molecular Weight
    Surface plasmon resonance
    Medicine
    Labels
    Molecular weight

    Cite this

    Aristotelous, Tonia ; Ahn, Seungkirl ; Shukla, Arun K. ; Gawron, Sylwia ; Sassano, Maria F. ; Kahsai, Alem W. ; Wingler, Laura M. ; Zhu, Xiao ; Tripathi-Shukla, Prachi ; Huang, Xi-Ping ; Riley, Jennifer ; Besnard, Jeremy ; Read, Kevin D. ; Roth, Bryan L. ; Gilbert, Ian H. ; Hopkins, Andrew L. ; Lefkowitz, Robert J. ; Navratilova, Iva. / Discovery of Β2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor. In: ACS Medicinal Chemistry Letters. 2013 ; Vol. 4, No. 10. pp. 1005-1010.
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    title = "Discovery of Β2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor",
    abstract = "G-protein coupled receptors (GPCRs) are the primary target class of currently marketed drugs, accounting for about a quarter of all drug targets of approved medicines. However, almost all the screening efforts for novel ligand discovery rely exclusively on cellular systems overexpressing the receptors. An alternative ligand discovery strategy is a fragment-based drug discovery, where low molecular weight compounds, known as fragments, are screened as initial starting points for optimization. However, the screening of fragment libraries usually employs biophysical screening methods, and as such, it has not been routinely applied to membrane proteins. We present here a surface plasmon resonance biosensor approach that enables, cell-free, label-free, fragment screening that directly measures fragment interactions with wild-type GPCRs. We exemplify the method by the discovery of novel, selective, high affinity antagonists of human {\^I}²2 adrenoceptor.",
    author = "Tonia Aristotelous and Seungkirl Ahn and Shukla, {Arun K.} and Sylwia Gawron and Sassano, {Maria F.} and Kahsai, {Alem W.} and Wingler, {Laura M.} and Xiao Zhu and Prachi Tripathi-Shukla and Xi-Ping Huang and Jennifer Riley and Jeremy Besnard and Read, {Kevin D.} and Roth, {Bryan L.} and Gilbert, {Ian H.} and Hopkins, {Andrew L.} and Lefkowitz, {Robert J.} and Iva Navratilova",
    year = "2013",
    doi = "10.1021/ml400312j",
    language = "English",
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    pages = "1005--1010",
    journal = "ACS Medicinal Chemistry Letters",
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    Aristotelous, T, Ahn, S, Shukla, AK, Gawron, S, Sassano, MF, Kahsai, AW, Wingler, LM, Zhu, X, Tripathi-Shukla, P, Huang, X-P, Riley, J, Besnard, J, Read, KD, Roth, BL, Gilbert, IH, Hopkins, AL, Lefkowitz, RJ & Navratilova, I 2013, 'Discovery of Β2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor', ACS Medicinal Chemistry Letters, vol. 4, no. 10, pp. 1005-1010. https://doi.org/10.1021/ml400312j

    Discovery of Β2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor. / Aristotelous, Tonia; Ahn, Seungkirl; Shukla, Arun K.; Gawron, Sylwia; Sassano, Maria F.; Kahsai, Alem W.; Wingler, Laura M.; Zhu, Xiao; Tripathi-Shukla, Prachi; Huang, Xi-Ping; Riley, Jennifer; Besnard, Jeremy; Read, Kevin D.; Roth, Bryan L.; Gilbert, Ian H.; Hopkins, Andrew L. (Lead / Corresponding author); Lefkowitz, Robert J. (Lead / Corresponding author); Navratilova, Iva (Lead / Corresponding author).

    In: ACS Medicinal Chemistry Letters, Vol. 4, No. 10, 2013, p. 1005-1010.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Discovery of Β2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor

    AU - Aristotelous, Tonia

    AU - Ahn, Seungkirl

    AU - Shukla, Arun K.

    AU - Gawron, Sylwia

    AU - Sassano, Maria F.

    AU - Kahsai, Alem W.

    AU - Wingler, Laura M.

    AU - Zhu, Xiao

    AU - Tripathi-Shukla, Prachi

    AU - Huang, Xi-Ping

    AU - Riley, Jennifer

    AU - Besnard, Jeremy

    AU - Read, Kevin D.

    AU - Roth, Bryan L.

    AU - Gilbert, Ian H.

    AU - Hopkins, Andrew L.

    AU - Lefkowitz, Robert J.

    AU - Navratilova, Iva

    PY - 2013

    Y1 - 2013

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    AB - G-protein coupled receptors (GPCRs) are the primary target class of currently marketed drugs, accounting for about a quarter of all drug targets of approved medicines. However, almost all the screening efforts for novel ligand discovery rely exclusively on cellular systems overexpressing the receptors. An alternative ligand discovery strategy is a fragment-based drug discovery, where low molecular weight compounds, known as fragments, are screened as initial starting points for optimization. However, the screening of fragment libraries usually employs biophysical screening methods, and as such, it has not been routinely applied to membrane proteins. We present here a surface plasmon resonance biosensor approach that enables, cell-free, label-free, fragment screening that directly measures fragment interactions with wild-type GPCRs. We exemplify the method by the discovery of novel, selective, high affinity antagonists of human β2 adrenoceptor.

    U2 - 10.1021/ml400312j

    DO - 10.1021/ml400312j

    M3 - Article

    C2 - 24454993

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    SP - 1005

    EP - 1010

    JO - ACS Medicinal Chemistry Letters

    JF - ACS Medicinal Chemistry Letters

    SN - 1948-5875

    IS - 10

    ER -