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Bitopic Ligands Support the Presence of a Metastable Binding Site at the β 2 Adrenergic Receptor.

Birgit Isabel GaiserMia DanielsenXinyu XuKira Røpke JørgensenPhilipp FronikEmil Märcher RørstedTomasz M WróbelXiangyu LiuJesper Mosolff MathiesenDaniel Sejer Pedersen
Published in: Journal of medicinal chemistry (2024)
Metastable binding sites (MBS) have been observed in a multitude of molecular dynamics simulations and can be considered low affinity allosteric binding sites (ABS) that function as stepping stones as the ligand moves toward the orthosteric binding site (OBS). Herein, we show that MBS can be utilized as ABS in ligand design, resulting in ligands with improved binding kinetics. Four homobivalent bitopic ligands ( 1 - 4 ) were designed by molecular docking of ( S )-alprenolol (( S )-ALP) in the cocrystal structure of the β 2 adrenergic receptor (β 2 AR) bound to the antagonist ALP. Ligand 4 displayed a potency and affinity similar to ( S )-ALP, but with a >4-fold increase in residence time. The proposed binding mode was confirmed by X-ray crystallography of ligand 4 in complex with the β 2 AR. This ligand design principle can find applications beyond the β 2 AR and G protein-coupled receptors (GPCRs) as a general approach for improving the pharmacological profile of orthosteric ligands by targeting the OBS and an MBS simultaneously.
Keyphrases
  • molecular dynamics simulations
  • molecular docking
  • binding protein
  • high resolution
  • computed tomography
  • magnetic resonance imaging
  • magnetic resonance