State-dependent dissociation of HERG channel inhibitors

Stork, Daniela; Windisch, Andreas; Timin, E. N.; Hohaus, Annette; Auer, Manfred; Ecker, Gerhard; Hering, Steffen

doi:10.1186/1471-2210-7-s2-a13

Cited by 14 publications

(22 citation statements)

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“…[15,19,44] Molecular modeling and docking studies Preparation of molecular structures: The structures of propafenone and its derivatives were built in MOL2 format using the sketcher module of Sybyl, and Gasteiger-Hückel charges were as-…”

Section: Methodsmentioning

confidence: 99%

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The hERG Potassium Channel and Drug Trapping: Insight from Docking Studies with Propafenone Derivatives

et al. 2010

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The inner cavity of the hERG potassium ion channel can accommodate large, structurally diverse compounds that can be trapped in the channel by closure of the activation gate. A small set of propafenone derivatives was synthesized, and both use-dependency and recovery from block were tested in order to gain insight into the behavior of these compounds with respect to trapping and non-trapping. Ligand-protein docking into homology models of the closed and open state of the hERG channel provides the first evidence for the molecular basis of drug trapping.

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Section: Methodsmentioning

confidence: 99%

“…[a] Values are the mean of three experiments and were measured in heterologous hERG expressed in X. laevis oocytes. [15,19,44] [b] Not determined. ure 2 C, D).…”

Section: Trapping Of Propafenone Derivativesmentioning

confidence: 99%

The hERG Potassium Channel and Drug Trapping: Insight from Docking Studies with Propafenone Derivatives

et al. 2010

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“…Our kinetic modeling studies have also enabled, for the first time, an estimation of the binding affinities for both the open and inactivated states for a range of drugs. Stork et al (2007) have recently published data extending the concept of state dependence to the dissociation of drugs from the hERG channel. As they have elegantly shown, some drugs require opening of the activation gate to dissociate from the inner cavity of the channel.…”

Section: Discussionmentioning

confidence: 99%

Drug Binding to the Inactivated State Is Necessary but Not Sufficient for High-Affinity Binding to Human Ether-à-go-go-Related Gene Channels

Perrin

Kuchel²,

Campbell³

et al. 2008

Mol Pharmacol

123

168

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Drug block of the human ether-à -go-go-related gene Kϩ channel (hERG) is the most common cause of acquired long QT syndrome, a disorder of cardiac repolarization that may result in ventricular tachycardia and sudden cardiac death. We investigated the open versus inactivated state dependence of drug block by using hERG mutants N588K and N588E, which shift the voltage dependence of inactivation compared with wildtype but in which the mutated residue is remote from the drug-binding pocket in the channel pore. Four high-affinity drugs (cisapride, dofetilide, terfenadine, and astemizole) demonstrated lower affinity for the inactivation-deficient N588K mutant hERG channel compared with N588E and wild-type hERG. Three of four low-affinity drugs (erythromycin, perhexiline, and quinidine) demonstrated no preference for N588E over N588K channels, whereas dl-sotalol was an example of a low-affinity state-dependent blocker. All five state-dependent blockers showed an even lower affinity for S620T mutant hERG (no inactivation) compared with N588K mutant hERG (greatly reduced inactivation). Computer modeling indicates that the reduced affinity for S620T compared with N588K and wild-type channels can be explained by the relative kinetics of drug block and unblock compared with the kinetics of inactivation and recovery from inactivation. We were also able to calculate, for the first time, the relative affinities for the inactivated versus the open state, which for the drugs tested here ranged from 4-to 70-fold. Our results show that preferential binding to the inactivated state is necessary but not sufficient for high-affinity binding to hERG channels.

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“…In this study we considered only a single drug-binding site and did not include state-dependent binding, i.e., specific kinetics of drug interaction with open and inactive states of K V 11.1 (Stork et al, 2007, Perrin et al, 2008, Hill et al, 2014. In previous studies of the antipsychotic clozapine, we measured fast and slow components to both block and unblock that corresponded to binding to the open and inactivated states, respectively (Hill et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Temperature Effects on Kinetics of K_V11.1 Drug Block Have Important Consequences for In Silico Proarrhythmic Risk Prediction

et al. 2016

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Drug block of voltage-gated potassium channel subtype 11.1 human ether-a-go-go related gene (K v 11.1) (hERG) channels, encoded by the KCNH2 gene, is associated with reduced repolarization of the cardiac action potential and is the predominant cause of acquired long QT syndrome that can lead to fatal cardiac arrhythmias. Current safety guidelines require that potency of K V 11.1 block is assessed in the preclinical phase of drug development. However, not all drugs that block K V 11.1 are proarrhythmic, meaning that screening on the basis of equilibrium measures of block can result in high attrition of potentially low-risk drugs. The basis of the next generation of drug-screening approaches is set to be in silico risk prediction, informed by in vitro mechanistic descriptions of drug binding, including measures of the kinetics of block. A critical issue in this regard is characterizing the temperature dependence of drug binding. Specifically, it is important to address whether kinetics relevant to physiologic temperatures can be inferred or extrapolated from in vitro data gathered at room temperature in high-throughout systems. Here we present the first complete study of the temperature-dependent kinetics of block and unblock of a proarrhythmic drug, cisapride, to K V 11.1. Our data highlight a complexity to binding that manifests at higher temperatures and can be explained by accumulation of an intermediate, non-blocking encounter-complex. These results suggest that for cisapride, physiologically relevant kinetic parameters cannot be simply extrapolated from those measured at lower temperatures; rather, data gathered at physiologic temperatures should be used to constrain in silico models that may be used for proarrhythmic risk prediction.

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State-dependent dissociation of HERG channel inhibitors

Cited by 14 publications

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The hERG Potassium Channel and Drug Trapping: Insight from Docking Studies with Propafenone Derivatives

The hERG Potassium Channel and Drug Trapping: Insight from Docking Studies with Propafenone Derivatives

Drug Binding to the Inactivated State Is Necessary but Not Sufficient for High-Affinity Binding to Human Ether-à-go-go-Related Gene Channels

Temperature Effects on Kinetics of K_V11.1 Drug Block Have Important Consequences for In Silico Proarrhythmic Risk Prediction

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State-dependent dissociation of HERG channel inhibitors

Cited by 14 publications

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The hERG Potassium Channel and Drug Trapping: Insight from Docking Studies with Propafenone Derivatives

The hERG Potassium Channel and Drug Trapping: Insight from Docking Studies with Propafenone Derivatives

Drug Binding to the Inactivated State Is Necessary but Not Sufficient for High-Affinity Binding to Human Ether-à-go-go-Related Gene Channels

Temperature Effects on Kinetics of KV11.1 Drug Block Have Important Consequences for In Silico Proarrhythmic Risk Prediction

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Temperature Effects on Kinetics of K_V11.1 Drug Block Have Important Consequences for In Silico Proarrhythmic Risk Prediction