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Kv 11.1 (hERG)-induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv 11.1
Z Yu1, A P IJzerman, L H Heitman
1Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Insights
Drug-induced arrhythmia is linked to Kv 11.1 channel blockade. Compound affinity for the Kv 11.1 channel depends on association rates, not lipophilicity, offering insights into cardiotoxicity mechanisms.
Area of Science:
- Pharmacology
- Cardiovascular Science
- Drug Discovery
Background:
- Drug-induced arrhythmia is a significant side effect linked to Kv 11.1 channel (hERG) blockade.
- Previous research focused on drug equilibrium parameters (affinity/potency) at the channel.
- Understanding drug-channel interaction kinetics is crucial for predicting and mitigating cardiotoxicity.
Purpose of the Study:
- To determine the binding kinetics of known Kv 11.1 channel blockers.
- To investigate the correlation between kinetic parameters, affinity, and physicochemical properties.
- To provide insights into the mechanism of Kv 11.1 channel interaction for safer drug development.
Main Methods:
- Utilized a novel [(3)H]-dofetilide competition association assay to measure binding kinetics.
- Evaluated 15 prototypical Kv 11.1 inhibitors.
- Determined compound lipophilicity (logKW - C8) and membrane partitioning (logKW - IAM) via HPLC.
Main Results:
- Validated a new assay for determining Kv 11.1 blocker binding kinetics.
- Found that compound affinity (Ki values) correlated with association rates, not dissociation rates.
- Observed no correlation between lipophilicity/membrane partitioning and affinity or rate constants.
Conclusions:
- Compound affinity for the Kv 11.1 channel is primarily determined by its association rate.
- Lipophilicity and membrane affinity do not dictate Kv 11.1 channel binding.
- Findings offer new understanding of Kv 11.1 channel activity, aiding in the prevention of drug-induced cardiotoxicity.
Background And Purpose:
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.
Experimental Approach:
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.
Key Results:
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.
Conclusions And Implications:
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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