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

Birgit I Gaiser; Mia Danielsen; Emil Marcher-Rørsted; Kira Røpke Jørgensen; Tomasz M Wróbel; Mikael Frykman; Henrik Johansson; Hans Bräuner-Osborne; David E Gloriam; Jesper Mosolff Mathiesen; Daniel Sejer Pedersen

doi:10.1021/acs.jmedchem.9b00595

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

Birgit I Gaiser, Mia Danielsen, Emil Marcher-Rørsted, Kira Røpke Jørgensen, Tomasz M Wróbel, Mikael Frykman, Henrik Johansson, Hans Bräuner-Osborne, David E Gloriam, Jesper Mosolff Mathiesen, Daniel Sejer Pedersen

Department of Drug Design and Pharmacology

3 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	17
Pages (from-to)	7806-7839
Number of pages	34
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.9b00595
Publication status	Published - 12 Sept 2019

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Gaiser, B. I., Danielsen, M., Marcher-Rørsted, E., Røpke Jørgensen, K., Wróbel, T. M., Frykman, M., Johansson, H., Bräuner-Osborne, H., Gloriam, D. E., Mathiesen, J. M., & Sejer Pedersen, D. (2019). Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands. Journal of Medicinal Chemistry, 62(17), 7806-7839. https://doi.org/10.1021/acs.jmedchem.9b00595

Gaiser, BI, Danielsen, M, Marcher-Rørsted, E, Røpke Jørgensen, K, Wróbel, TM, Frykman, M, Johansson, H, Bräuner-Osborne, H , Gloriam, DE , Mathiesen, JM & Sejer Pedersen, D 2019, 'Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands', Journal of Medicinal Chemistry, vol. 62, no. 17, pp. 7806-7839. https://doi.org/10.1021/acs.jmedchem.9b00595

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

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.",

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AU - Gaiser, Birgit I

AU - Danielsen, Mia

AU - Marcher-Rørsted, Emil

AU - Røpke Jørgensen, Kira

AU - Wróbel, Tomasz M

AU - Frykman, Mikael

AU - Johansson, Henrik

AU - Bräuner-Osborne, Hans

AU - Gloriam, David E

AU - Mathiesen, Jesper Mosolff

AU - Sejer Pedersen, Daniel

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N2 - 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.

AB - 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.

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DO - 10.1021/acs.jmedchem.9b00595

M3 - Journal article

C2 - 31298548

SN - 0022-2623

VL - 62

SP - 7806

EP - 7839

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 17

ER -

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

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