Discovery of β2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • October 10, 2013

Published In

Volume / Issue

  • 4 / 10

Start / End Page

  • 1005 - 1010

PubMed ID

  • 24454993

Pubmed Central ID

  • PMC3892729

International Standard Serial Number (ISSN)

  • 1948-5875

Digital Object Identifier (DOI)

  • 10.1021/ml400312j


  • eng

Conference Location

  • United States