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Author

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, Gaiser, Birgit Isabel, Danielsen, Mia, Xu, Xinyu, Røpke Jørgensen, Kira, Fronik, Philipp, Märcher-Rørsted, Emil, Wróbel, Tomasz M., Liu, Xiangyu, Mosolff Mathiesen, Jesper, and Sejer Pedersen, Daniel

Published
2024

5. Bitopic Ligands Support the Presence of a Metastable Binding Site at the β2Adrenergic Receptor

Author

Gaiser, Birgit Isabel, Danielsen, Mia, Xu, Xinyu, Røpke Jørgensen, Kira, Fronik, Philipp, Märcher-Rørsted, Emil, Wróbel, Tomasz M., Liu, Xiangyu, Mosolff Mathiesen, Jesper, and Sejer Pedersen, Daniel

Abstract

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.

Published
2024
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6. Structure–Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands

Author

Fronik, Philipp, primary, Poetsch, Isabella, additional, Kastner, Alexander, additional, Mendrina, Theresa, additional, Hager, Sonja, additional, Hohenwallner, Katharina, additional, Schueffl, Hemma, additional, Herndler-Brandstetter, Dietmar, additional, Koellensperger, Gunda, additional, Rampler, Evelyn, additional, Kopecka, Joanna, additional, Riganti, Chiara, additional, Berger, Walter, additional, Keppler, Bernhard K., additional, Heffeter, Petra, additional, and Kowol, Christian R., additional

Published
2021
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7. Albumin-targeting of an oxaliplatin-releasing platinum(iv) prodrug results in pronounced anticancer activity due to endocytotic drug uptake in vivo

Author

Schueffl, Hemma, primary, Theiner, Sarah, additional, Hermann, Gerrit, additional, Mayr, Josef, additional, Fronik, Philipp, additional, Groza, Diana, additional, van Schonhooven, Sushilla, additional, Galvez, Luis, additional, Sommerfeld, Nadine S., additional, Schintlmeister, Arno, additional, Reipert, Siegfried, additional, Wagner, Michael, additional, Mader, Robert M., additional, Koellensperger, Gunda, additional, Keppler, Bernhard K., additional, Berger, Walter, additional, Kowol, Christian R., additional, Legin, Anton, additional, and Heffeter, Petra, additional

Published
2021
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8. Bitopic Ligands and Metastable Binding Sites:Opportunities for G Protein-Coupled Receptor (GPCR) Medicinal Chemistry

Author

Fronik, Philipp, Gaiser, Birgit I, Sejer Pedersen, Daniel, Fronik, Philipp, Gaiser, Birgit I, and Sejer Pedersen, Daniel

Abstract

G protein-coupled receptors (GPCRs) belong to a large superfamily of membrane receptors mediating a variety of physiological functions. As such they are attractive targets for drug therapy. However, it remains a challenge to develop subtype selective GPCR ligands due to the high conservation of orthosteric binding sites. Bitopic ligands have been employed to address the selectivity problem by combining (linking) an orthosteric ligand with an allosteric modulator, theoretically leading to high-affinity subtype selective ligands. However, it remains a challenge to identify suitable allosteric binding sites. Computational studies on ligand binding to GPCRs have revealed transient, low-affinity binding sites, termed metastable binding sites. Metastable binding sites may provide a new source of allosteric binding sites that could be exploited in the design of bitopic ligands. Unlike the bitopic ligands that have been reported to date, this type of bitopic ligands would be composed of two identical pharmacophores. Herein, we outline the concept of bitopic ligands, review metastable binding sites, and discuss their potential as a new source of allosteric binding sites.

Published
2017

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

Author

Gaiser BI, Danielsen M, Xu X, Røpke Jørgensen K, Fronik P, Märcher-Rørsted E, Wróbel TM, Liu X, Mosolff Mathiesen J, and Sejer Pedersen D

Subjects
Ligands, Humans, Binding Sites, Crystallography, X-Ray, Alprenolol chemistry, Alprenolol pharmacology, Alprenolol metabolism, Adrenergic beta-2 Receptor Antagonists chemistry, Adrenergic beta-2 Receptor Antagonists pharmacology, Adrenergic beta-2 Receptor Antagonists metabolism, Molecular Dynamics Simulation, Drug Design, Receptors, Adrenergic, beta-2 metabolism, Receptors, Adrenergic, beta-2 chemistry, Molecular Docking Simulation
Abstract

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.

Published
2024
Full Text
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