| Autor: |
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 |
| Zdroj: |
Journal of Medicinal Chemistry; July 2024, Vol. 67 Issue: 13 p11053-11068, 16p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
