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Halogen-aromatic π-interactions modulate inhibitor residence time

DOI: 10.1002/anie.201801666 DOI Help

Authors: Christina Heroven (University of Oxford) , Victoria Georgi (Bayer AG) , Gaurav K. Ganotra (Heidelberg Institute for Theoretical Studies (HITS); Heidelberg University) , Paul E. Brennan (Structural Genomics Consortium, University of Oxford; Target Discovery Institute) , Finn Wolfreys (Structural Genomics Consortium, University of Oxford; Target Discovery Institute) , Rebecca C. Wade , Amaury E. Fernández-Montalván (Bayer AG) , Apirat Chaikuad (Structural Genomics Consortium, University of Oxford; Johann Wolfgang Goethe-University;) , Stefan Knapp (Structural Genomics Consortium, University of Oxford; Johann Wolfgang Goethe-University; German Cancer Network (DKTK))
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: March 2018
Diamond Proposal Number(s): 10619

Abstract: Prolonged drug residence times may result in longer lasting drug efficacy, improved pharmacodynamic properties and "kinetic selectivity" over off-targets with fast 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. Here, 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. This key interaction is dependent on the interactions with an aromatic residue in the gatekeeper position and we observe this interaction in other kinases with an aromatic gatekeeper residue. We provide a detailed mechanistic characterization of the halogen-aromatic π interactions in the haspin-inhibitor complexes by means of kinetic, thermodynamic, and structural measurements along with binding energy calculations. Since halogens are frequently used in drugs and aromatic residues are often present in the binding sites of proteins, our results provide a compelling rationale for introducing aromatic-halogen interactions to prolong drug-target residence times.

Journal Keywords: Halogen-π interaction; drug residence time; kinase; Haspin; CLK1

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 18/04/2018 15:26

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)