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The Utility of Drug Residence Time for the Assessment of Inhibitor Potency


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February 04, 2016

Authors: Brad Larson, Peter Banks, BioTek Instruments, Inc. Winooski, VT USA; Arturo Gonzalez-Moya, Cisbio US, Inc. Bedford MA USA



Drug-target residence time is becoming increasingly recognized as a critical parameter for the assessment of drug potency. Inhibition of the target protein’s activity can only take place when the drug is bound, which is governed by the affinity of the compound for the target, as well as the dissociative off-rate of the compound from the drug-target complex. Traditionally, drug-target residence time studies have been performed in late stage preclinical studies using radio-labeled compounds, but many programs now desire to probe hits from screens which require technologies that provide greater sample throughput.

Here we describe the ultility of the Tag-lite detection technology for performing high throughput kinetic ligand binding using a microplate reader. This HTS mix-and-ready technology is suitable for assessing many compounds rapidly. The microplate reader requirements are principally governed by the need for high temporal resolution without sacrificing sensitivity for the accurate assessment of drug-target kinetic parameters. A case study using CXCR4 and its natural ligand, CXCL12 was chosen to demonstrate the determination of the residence time for AMD 3465, a known CXCR4 inhibitor. A comparison of both kinetic and thermodynamic ligand and competitor binding was performed.

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