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Kv 11.1 (hERG)-induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv 11.1 (hERG) inhibitors

Source: Br. J. Pharmacol., Volume 172, Issue 3, pp. 940-55 (2015)

Yu, Z.; IJzerman, A.P.; Heitman, L.H.
15 December 2014
Online publication


Drug-induced arrhythmia due to blockade of the Kv 11.1 channel (also known as the hERG K(+) channel) is a frequent side effect. Previous studies have primarily focused on equilibrium parameters, i.e. affinity or potency, of drug candidates at the channel. The aim of this study was to determine the kinetics of the interaction with the channel for a number of known Kv 11.1 blockers and to explore a possible correlation with the affinity or physicochemical properties of these compounds.


The affinity and kinetic parameters of 15 prototypical Kv 11.1 inhibitors were evaluated in a number of [(3) H]-dofetilide binding assays. The lipophilicity (logKW - C8 ) and membrane partitioning (logKW - IAM ) of these compounds were determined by means of HPLC analysis.


A novel [(3) H]-dofetilide competition association assay was set up and validated, which allowed us to determine the binding kinetics of the Kv 11.1 blockers used in this study. Interestingly, the compounds' affinities (Ki values) were correlated to their association rates rather than dissociation rates. Overall lipophilicity or membrane partitioning of the compounds were not correlated to their affinity or rate constants for the channel.


A compound's affinity for the Kv 11.1 channel is determined by its rate of association with the channel, while overall lipophilicity and membrane affinity are not. In more general terms, our findings provide novel insights into the mechanism of action for a compound's activity at the Kv 11.1 channel. This may help to elucidate how Kv 11.1-induced cardiotoxicity is governed and how it can be circumvented in the future.

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