Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 54, Issue 47, Pages 14099-14102Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201505800
Keywords
covalent inhibitors; drug discovery; irreversible inhibition; enzyme kinetics
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Owing to their covalent target occupancy, irreversible inhibitors require low exposures and offer long duration, and their use thus represents a powerful strategy for achieving pharmacological efficacy. Importantly, the potency metric of irreversible inhibitors is k(inact)/K-I not IC50. A simple approach to measuring k(inact)/K-I was developed that makes use of an irreversible probe for competitive assays run to completion against test compounds. In this system, the k(inact)/K-I value of the test compound is equal to (k(inact)/K-I) probe x [probe]/IC50. The advantages of this method include simplicity, high throughput, and application to all target classes, and it only requires an indepth kinetic evaluation of the probe.
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