BiophysicalFragment Screening of the β1-Adrenergic Receptor:Identification of High Affinity Arylpiperazine Leads Using Structure-BasedDrug Design

摘要

Biophysical fragment screening of a thermostabilized β1-adrenergic receptor (β1AR) 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 β1AR 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 β1AR complexed with >19 and >20 were determined at resolutions of 2.8 and 2.7 Å, respectively.