Biophysical Fragment Screening of the β(1)-Adrenergic Receptor: Identification of High Affinity Arylpiperazine Leads Using Structure-Based Drug Design

[Image: see text] Biophysical fragment screening of a thermostabilized β(1)-adrenergic receptor (β(1)AR) using surface plasmon resonance (SPR) enabled the identification of moderate affinity, high ligand efficiency (LE) arylpiperazine hits 7 and 8. Subsequent hit to lead follow-up confirmed the activity of the chemotype, and a structure-based design approach using protein–ligand crystal structures of the β(1)AR resulted in the identification of several fragments that bound with higher affinity, including indole 19 and quinoline 20. In the first example of GPCR crystallography with ligands derived from fragment screening, structures of the stabilized β(1)AR complexed with 19 and 20 were determined at resolutions of 2.8 and 2.7 Å, respectively.