A Focus on Unusual ECL2 Interactions Yields β2‐Adrenergic Receptor Antagonists with Unprecedented Scaffolds. (17th April 2020)

• Record Type: Journal Article
• Authors: Scharf, Magdalena M.; Zimmermann, Mirjam; Wilhelm, Florian; Stroe, Raimond; Waldhoer, Maria; Kolb, Peter
• Is Part Of: ChemMedChem. Volume 15:Number 10(2020)
• Page Start: 882
• Page End: 890
• Publication Date: 2020-04-17
• Subjects: beta2-adrenergic receptor ligands -- drug design -- G protein-coupled receptors -- ligand scaffolds -- virtual screening; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900715
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : Picking pocket parts : Exploring interactions with a different part of the binding pocket of the β2 ‐adrenergic receptor than usually targeted yielded antagonists with a novel scaffold. This also showed that new structures and docking studies can yield novel ligands even for well‐described receptors.