A Focus on Unusual ECL2 Interactions Yields β2 -Adrenergic Receptor Antagonists with Unprecedented Scaffolds

Abstract

The binding pockets of aminergic G protein-coupled receptors are often targeted by drugs and virtual screening campaigns. In order to find ligands with unprecedented scaffolds for one of the best-investigated receptors of this subfamily, the β₂ -adrenergic receptor, we conducted a docking-based screen insisting that molecules would address previously untargeted residues in extracellular loop 2. We here report the discovery of ligands with a previously undescribed coumaran-based scaffold. Furthermore, we provide an analysis of the added value that X-ray structures in different conformations deliver for such docking screens.

Keywords: G protein-coupled receptors; beta2-adrenergic receptor ligands; drug design; ligand scaffolds; virtual screening.