Halogen–Aromatic π Interactions Modulate Inhibitor Residence Times |
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| Authors: | Christina Heroven Victoria Georgi Gaurav K Ganotra Prof Paul Brennan Finn Wolfreys Prof Dr Rebecca C Wade Amaury E Fernández‐Montalván Apirat Chaikuad Prof Dr Stefan Knapp |
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| Institution: | 1. Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, UK;2. Bayer AG, Drug Discovery, Pharmaceuticals, Lead Discovery Berlin, Berlin, Germany;3. Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany;4. Heidelberg Graduate School of Mathematical and Computational Methods for the Sciences, Heidelberg University, Heidelberg, Germany;5. Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK;6. Zentrum für Molekulare Biologie der Universit?t Heidelberg, DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany;7. Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany;8. Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany;9. Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany;10. German Cancer Network (DKTK), Frankfurt/Mainz site, Frankfurt am Main, Germany |
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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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| Keywords: | drug residence times halogen– π interactions iodine kinases proteins |
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