TY - JOUR

T1 - Bitopic Ligands Support the Presence of a Metastable Binding Site at the β2 Adrenergic Receptor

AU - Gaiser, Birgit Isabel

AU - Danielsen, Mia

AU - Xu, Xinyu

AU - Røpke Jørgensen, Kira

AU - Fronik, Philipp

AU - Märcher-Rørsted, Emil

AU - Wróbel, Tomasz M.

AU - Liu, Xiangyu

AU - Mosolff Mathiesen, Jesper

AU - Sejer Pedersen, Daniel

N1 - Publisher Copyright: © 2024 American Chemical Society.

PY - 2024

Y1 - 2024

N2 - 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 β2 adrenergic receptor (β2AR) 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 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.

AB - 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 β2 adrenergic receptor (β2AR) 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 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.

U2 - 10.1021/acs.jmedchem.4c00578

DO - 10.1021/acs.jmedchem.4c00578

M3 - Journal article

C2 - 38952152

AN - SCOPUS:85197294321

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

ER -