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Halogen-aromatic π interactions modulate inhibitor residence times

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 integra...

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Main Authors: Heroven, Christina (Author) , Georgi, Victoria (Author) , Ganotra, Gaurav K. (Author) , Brennan, Paul (Author) , Wolfreys, Finn (Author) , Wade, Rebecca C. (Author) , Fernández‐Montalván, Amaury E. (Author) , Chaikuad, Apirat (Author) , Knapp, Stefan (Author)
Format: Article (Journal)
Language:English
Published: 30 March 2018
In: Angewandte Chemie. International edition
Year: 2018, Volume: 57, Issue: 24, Pages: 7220-7224
ISSN:1521-3773
DOI:10.1002/anie.201801666
Online Access:Verlag, Volltext: https://doi.org/10.1002/anie.201801666
Verlag, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201801666
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Author Notes: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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Summary: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.
Item Description:First published: 30 March 2018
Gesehen am 19.12.2019
Physical Description:Online Resource
ISSN:1521-3773
DOI:10.1002/anie.201801666

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