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Nat Chem Biol. 2015 Jun;11(6):416-23. doi: 10.1038/nchembio.1796. Epub 2015 Apr 20.

Translating slow-binding inhibition kinetics into cellular and in vivo effects.

Author information

1
Infection Innovative Medicines Unit, AstraZeneca Research and Development, Waltham, Massachusetts, USA.
2
Institute for Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, New York, USA.
3
Department of Oral Biology and Pathology, Stony Brook University, Stony Brook, New York, USA.

Abstract

Many drug candidates fail in clinical trials owing to a lack of efficacy from limited target engagement or an insufficient therapeutic index. Minimizing off-target effects while retaining the desired pharmacodynamic (PD) response can be achieved by reduced exposure for drugs that display kinetic selectivity in which the drug-target complex has a longer half-life than off-target-drug complexes. However, though slow-binding inhibition kinetics are a key feature of many marketed drugs, prospective tools that integrate drug-target residence time into predictions of drug efficacy are lacking, hindering the integration of drug-target kinetics into the drug discovery cascade. Here we describe a mechanistic PD model that includes drug-target kinetic parameters, including the on- and off-rates for the formation and breakdown of the drug-target complex. We demonstrate the utility of this model by using it to predict dose response curves for inhibitors of the LpxC enzyme from Pseudomonas aeruginosa in an animal model of infection.

PMID:
25894085
PMCID:
PMC4536915
DOI:
10.1038/nchembio.1796
[Indexed for MEDLINE]
Free PMC Article

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