Bitopic Ligands Support the Presence of a Metastable Binding Site at the ß2 Adrenergic Receptor.
J Med Chem
; 67(13): 11053-11068, 2024 Jul 11.
Article
in En
| MEDLINE
| ID: mdl-38952152
ABSTRACT
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 ß2 adrenergic receptor (ß2AR) 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 ß2AR. This ligand design principle can find applications beyond the ß2AR 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, Adrenergic, beta-2
/
Molecular Docking Simulation
Limits:
Humans
Language:
En
Journal:
J Med Chem
Year:
2024
Document type:
Article