A Focus on Unusual ECL2 Interactions Yields β 2 -Adrenergic Receptor Antagonists with Unprecedented Scaffolds

ChemMedChem. 2020 May 19;15(10):882-890. doi: 10.1002/cmdc.201900715. Epub 2020 Apr 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Antagonists / chemistry
  • Adrenergic beta-2 Receptor Antagonists / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Structure-Activity Relationship

Substances

  • Adrenergic beta-2 Receptor Antagonists
  • Receptors, Adrenergic, beta-2