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Rapid hit confirmation and early hERG liability testing using the IonWorks HT system

IONWORKS HT APPLICATION NOTE #4

By James Costantin, Ph.D., Yen-Wen Chen, Ph.D., Jinfang Liao, Ph.D., Jeff Quast, Andrew Wittel, Shawn Handran, Ph.D. and Naibo Yang, Ph.D. Molecular Devices Corporation, 3280 Whipple Road, Union City, CA 94587.


INTRODUCTION
Voltage-dependent ion channels represent a largely untapped portion of the potential drug target market.1 Until recently, voltage-dependent ion channels have been studied during the drug discovery process either using indirect methods of measuring the presence or activity of ion channels or by the gold standard patch clamp technique. Some of the higher throughput, lower content techniques include binding and flux assays, and the use of fluorescent dyes.2 While these assays have proven useful, they lack the ability to maintain a population of ion channels in a particular conformational state due to the lack of voltage control. The traditional patch clamp technique is labor intensive but offers direct control of the membrane potential and a direct measurement of ionic current. Thus, a population of channels can be driven to a particular conformational state, which may affect drug binding. The low throughput conventional patch clamp technique creates a severe bottleneck in following up on the hits from upstream indirect ion channel assays.3

This application note illustrates how the IonWorks HT system can be used to rapidly confirm hits from higher-throughput assays as well as perform earl
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