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

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

N2 - 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.

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

SN - 1948-5875

VL - 4

SP - 1005

EP - 1010

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 10

ER -