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| Verfasst von: | Heroven, Christina [VerfasserIn]  |
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| | Georgi, Victoria [VerfasserIn] |
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| | Ganotra, Gaurav K. [VerfasserIn] |
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| | Brennan, Paul [VerfasserIn] |
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| | Wolfreys, Finn [VerfasserIn] |
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| | Wade, Rebecca C. [VerfasserIn] |
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| | Fernández‐Montalván, Amaury E. [VerfasserIn] |
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| | Chaikuad, Apirat [VerfasserIn] |
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| | Knapp, Stefan [VerfasserIn] |
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| Titel: | Halogen-aromatic π interactions modulate inhibitor residence times |
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| Verf.angabe: | Christina Heroven, Victoria Georgi, Gaurav K. Ganotra, Paul Brennan, Finn Wolfreys, Rebecca C. Wade, Amaury E. Fernández‐Montalván, Apirat Chaikuad, Stefan Knapp |
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| E-Jahr: | 2018 |
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| Jahr: | 30 March 2018 |
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| Umfang: | 5 S. |
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| Fussnoten: | First published: 30 March 2018 ; Gesehen am 19.12.2019 |
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| Titel Quelle: | Enthalten in: Angewandte Chemie / International edition |
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| Ort Quelle: | Weinheim : Wiley-VCH, 1962 |
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| Jahr Quelle: | 2018 |
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| Band/Heft Quelle: | 57(2018), 24, Seite 7220-7224 |
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| ISSN Quelle: | 1521-3773 |
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| Abstract: | Prolonged drug residence times may result in longer-lasting drug efficacy, improved pharmacodynamic properties, and “kinetic selectivity” over off-targets with high drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Herein, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5-iodotubercidin (5-iTU) derivatives as a model for an archetypal active-state (type I) kinase-inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. The halogen-aromatic π interactions in the haspin-inhibitor complexes were characterized by means of kinetic, thermodynamic, and structural measurements along with binding-energy calculations. |
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| DOI: | doi:10.1002/anie.201801666 |
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| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
Volltext ; Verlag: https://doi.org/10.1002/anie.201801666 |
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| | Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201801666 |
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| | DOI: https://doi.org/10.1002/anie.201801666 |
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| Datenträger: | Online-Ressource |
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| Sprache: | eng |
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| Sach-SW: | Drug residence times |
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| | Halogen-π interactions |
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| | Iodine |
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| | Kinases |
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| | Proteins |
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| K10plus-PPN: | 1685960928 |
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| Verknüpfungen: | → Zeitschrift |
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Halogen-aromatic π interactions modulate inhibitor residence times / Heroven, Christina [VerfasserIn]; 30 March 2018 (Online-Ressource)
