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Bitopic Ligands Support the Presence of a Metastable Binding Site at the β2Adrenergic Receptor

Bitopic Ligands Support the Presence of a Metastable Binding Site at the β2Adrenergic Receptor

Authors :
Gaiser, Birgit Isabel
Danielsen, Mia
Xu, Xinyu
Røpke Jørgensen, Kira
Fronik, Philipp
Märcher-Rørsted, Emil
Wróbel, Tomasz M.
Liu, Xiangyu
Mosolff Mathiesen, Jesper
Sejer Pedersen, Daniel
Source :
Journal of Medicinal Chemistry; July 2024, Vol. 67 Issue: 13 p11053-11068, 16p
Publication Year :
2024

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 β2adrenergic receptor (β2AR) bound to the antagonist ALP. Ligand 4displayed 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 4in complex with the β2AR. This ligand design principle can find applications beyond the β2AR 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.

Details

Language :
English
ISSN :
00222623 and 15204804
Volume :
67
Issue :
13
Database :
Supplemental Index
Journal :
Journal of Medicinal Chemistry
Publication Type :
Periodical
Accession number :
ejs66808761
Full Text :
https://doi.org/10.1021/acs.jmedchem.4c00578