Bitopic Ligands Support the Presence of a Metastable Binding Site at the β 2 Adrenergic Receptor.

Autor:	Gaiser BI; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark., Danielsen M; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark., Xu X; State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084 ,China., Røpke Jørgensen K; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark., Fronik P; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark., Märcher-Rørsted E; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark., Wróbel TM; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.; Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, Chodźki 4a, 20093 Lublin, Poland., Liu X; State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084 ,China., Mosolff Mathiesen J; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark., Sejer Pedersen D; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Jul 11; Vol. 67 (13), pp. 11053-11068. Date of Electronic Publication: 2024 Jul 01.
DOI:	10.1021/acs.jmedchem.4c00578
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 β 2 adrenergic receptor (β 2 AR) 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 β 2 AR. This ligand design principle can find applications beyond the β 2 AR 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:	MEDLINE
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