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Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands

Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands

Authors :
Gaiser, Birgit I.
Danielsen, Mia
Marcher-Rørsted, Emil
Røpke Jørgensen, Kira
Wróbel, Tomasz M.
Frykman, Mikael
Johansson, Henrik
Bräuner-Osborne, Hans
Gloriam, David E.
Mathiesen, Jesper Mosolff
Sejer Pedersen, Daniel
Source :
Journal of Medicinal Chemistry; 20240101, Issue: Preprints
Publication Year :
2024

Abstract

Herein, we report the development of bitopic ligands aimed at targeting the orthosteric binding site (OBS) and a metastable binding site (MBS) within the same receptor unit. Previous molecular dynamics studies on ligand binding to the β2-adrenergic receptor (β2AR) suggested that ligands pause at transient, less-conserved MBSs. We envisioned that MBSs can be regarded as allosteric binding sites and targeted by homobivalent bitopic ligands linking two identical pharmacophores. Such ligands were designed based on docking of the antagonist (S)-alprenolol into the OBS and an MBS and synthesized. Pharmacological characterization revealed ligands with similar potency and affinity, slightly increased β2/β1AR-selectivity, and/or substantially slower β2AR off-rates compared to (S)-alprenolol. Truncated bitopic ligands suggested the major contribution of the metastable pharmacophore to be a hydrophobic interaction with the β2AR, while the linkers alone decreased the potency of the orthosteric fragment. Altogether, the study underlines the potential of targeting MBSs for improving the pharmacological profiles of ligands.

Details

Language :
English
ISSN :
00222623 and 15204804
Issue :
Preprints
Database :
Supplemental Index
Journal :
Journal of Medicinal Chemistry
Publication Type :
Periodical
Accession number :
ejs50588964
Full Text :
https://doi.org/10.1021/acs.jmedchem.9b00595