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 journalArticlepeer-review

    59 Citations (Scopus)


    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
    Issue number10
    Publication statusPublished - 2013


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