Halogen-Aromatic πInteractions Modulate Inhibitor Residence Times. Heroven, C., Georgi, V., Ganotra, G., K., Brennan, P., Wolfreys, F., Wade, R., C., Fernández-Montalván, A., E., Chaikuad, A., & Knapp, S. Angewandte Chemie - International Edition, 57(24):7220-7224, 3, 2018. doi abstract bibtex 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.
@article{
title = {Halogen-Aromatic πInteractions Modulate Inhibitor Residence Times},
type = {article},
year = {2018},
keywords = {Drug residence times,Halogen-π interactions,Iodine,Kinases,Proteins},
pages = {7220-7224},
volume = {57},
month = {3},
city = {University of Oxford, UNITED KINGDOM.},
id = {c8af04ff-3f9c-3b75-b3d6-c580d34c6014},
created = {2018-05-02T07:31:55.876Z},
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last_modified = {2018-07-09T12:39:49.735Z},
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citation_key = {heroven2018halogen-aromatictime.},
source_type = {article},
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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 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.},
bibtype = {article},
author = {Heroven, Christina and Georgi, Victoria and Ganotra, Gaurav K. and Brennan, Paul and Wolfreys, Finn and Wade, Rebecca C. and Fernández-Montalván, Amaury E. and Chaikuad, Apirat and Knapp, Stefan},
doi = {10.1002/anie.201801666},
journal = {Angewandte Chemie - International Edition},
number = {24}
}