Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors
Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors
Dokument öffnen (5.1MB)Datum der Veröffentlichung
21.04.2023Verlag / herausgebende Einrichtung
ElsevierVerlagsort
AmsterdamMetadaten
Zur Langanzeige
Zitierbarer Link (Handle URI) 
https://hdl.handle.net/20.500.11811/13551
Inhalt
The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gαq/11 proteins. They are important pharmacological tools and have potential as therapeutic drugs. The hydrogenated, tritium-labeled YM and FR derivatives display largely different residence times despite similar structures. In the present study we established a competition-association binding assay to determine the dissociation kinetics of unlabeled Gαq protein inhibitors. Structure-affinity and structure-residence time relationships were analyzed. Small structural modifications had a large impact on residence time. YM and FR exhibited 4- to 10-fold higher residence times than their hydrogenated derivatives. While FR showed pseudo-irreversible binding, YM displayed much faster dissociation from its target. The isopropyl anchor present in FR and some derivatives was essential for slow dissociation. These data provide a basis for future drug design toward modulating residence times of macrocyclic Gαq protein inhibitors, which has been recognized as a crucial determinant for therapeutic outcome.
Klassifikation (DDC)
615 Pharmakologie, TherapeutikErschienen in
iScience, 2023, vol. 26, iss. 4, 106492, S. 1-18Erstpublikation
https://doi.org/10.1016/j.isci.2023.106492Voss, Jan H.; Crüsemann, Max; Bartling, Christian R.O.; Kehraus, Stefan; Inoue, Asuka; König, Gabriele M.; Strømgaard, Kristian; Müller, Christa E.: Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors. In: iScience. 2023, vol. 26, iss. 4, 106492, 1-18.
Online-Ausgabe in bonndoc: https://hdl.handle.net/20.500.11811/13551
Online-Ausgabe in bonndoc: https://hdl.handle.net/20.500.11811/13551
@article{handle:20.500.11811/13551,
author = {{Jan H. Voss} and {Max Crüsemann} and {Christian R.O. Bartling} and {Stefan Kehraus} and {Asuka Inoue} and {Gabriele M. König} and {Kristian Strømgaard} and {Christa E. Müller}},
title = {Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors},
publisher = {Elsevier},
year = 2023,
month = apr,
journal = {iScience},
volume = 2023, vol. 26,
number = iss. 4, 106492,
pages = 1--18,
note = {The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gαq/11 proteins. They are important pharmacological tools and have potential as therapeutic drugs. The hydrogenated, tritium-labeled YM and FR derivatives display largely different residence times despite similar structures. In the present study we established a competition-association binding assay to determine the dissociation kinetics of unlabeled Gαq protein inhibitors. Structure-affinity and structure-residence time relationships were analyzed. Small structural modifications had a large impact on residence time. YM and FR exhibited 4- to 10-fold higher residence times than their hydrogenated derivatives. While FR showed pseudo-irreversible binding, YM displayed much faster dissociation from its target. The isopropyl anchor present in FR and some derivatives was essential for slow dissociation. These data provide a basis for future drug design toward modulating residence times of macrocyclic Gαq protein inhibitors, which has been recognized as a crucial determinant for therapeutic outcome.},
url = {https://hdl.handle.net/20.500.11811/13551}
}
author = {{Jan H. Voss} and {Max Crüsemann} and {Christian R.O. Bartling} and {Stefan Kehraus} and {Asuka Inoue} and {Gabriele M. König} and {Kristian Strømgaard} and {Christa E. Müller}},
title = {Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors},
publisher = {Elsevier},
year = 2023,
month = apr,
journal = {iScience},
volume = 2023, vol. 26,
number = iss. 4, 106492,
pages = 1--18,
note = {The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gαq/11 proteins. They are important pharmacological tools and have potential as therapeutic drugs. The hydrogenated, tritium-labeled YM and FR derivatives display largely different residence times despite similar structures. In the present study we established a competition-association binding assay to determine the dissociation kinetics of unlabeled Gαq protein inhibitors. Structure-affinity and structure-residence time relationships were analyzed. Small structural modifications had a large impact on residence time. YM and FR exhibited 4- to 10-fold higher residence times than their hydrogenated derivatives. While FR showed pseudo-irreversible binding, YM displayed much faster dissociation from its target. The isopropyl anchor present in FR and some derivatives was essential for slow dissociation. These data provide a basis for future drug design toward modulating residence times of macrocyclic Gαq protein inhibitors, which has been recognized as a crucial determinant for therapeutic outcome.},
url = {https://hdl.handle.net/20.500.11811/13551}
}
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