Kinetics of Drug Interaction with the K<sub>v</sub>11.1 Potassium Channel

Hill, Adam P.; Perrin, Mark; Heide, Juliane; Campbell, Terence J.; Mann, Stefan A.; Vandenberg, Jamie I.

doi:10.1124/mol.114.091835

Cited by 23 publications

(38 citation statements)

References 30 publications

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“…To assess the dose-response relationship for cisapride block of K V 11.1, we measured the degree of steady-state block observed at a constant holding potential of 0 mV, as previously described (Hill et al, 2014). After membrane depolarization, currents were allowed to reach a stable plateau before cisapride application at concentrations between 2 and 600 nM (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…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). For the present study, to focus on defining the mechanistic basis of temperature dependence of block, we chose a drug with simpler kinetics of interaction.…”

Section: Discussionmentioning

confidence: 99%

“…of four to eight cells. of ,30 milliseconds (Hill et al, 2014). The reusable Dynaflow system enabled delivery of discrete solutions of various drug concentrations under laminar flow.…”

Section: Patch-clamp Electrophysiologymentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

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“…Drug molecular binding to channel states with different conformations or a distinct affinity presents complex behaviours. In a recent study, Romero et al (2014) Based on experimental data on the effect of the antipsychotic clozapine on hERG channel blocking and unblocking kinetics, Hill et al (2014) proposed an hERG channel model with kinetically distinct binding states of the drug to open and inactivation states. Their modelling data effectively illustrated the interaction between clozapine and hERG channels in acquired LQT (Hill et al, 2014).…”

Section: Potassium Channel and Drug Interactionmentioning

confidence: 99%

The virtual heart as a platform for screening drug cardiotoxicity

Yuan

Bai

Luo

et al. 2015

British J Pharmacology

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To predict the safety of a drug at an early stage in its development is a major challenge as there is a lack of in vitro heart models that correlate data from preclinical toxicity screening assays with clinical results. A biophysically detailed computer model of the heart, the virtual heart, provides a powerful tool for simulating drug–ion channel interactions and cardiac functions during normal and disease conditions and, therefore, provides a powerful platform for drug cardiotoxicity screening. In this article, we first review recent progress in the development of theory on drug–ion channel interactions and mathematical modelling. Then we propose a family of biomarkers that can quantitatively characterize the actions of a drug on the electrical activity of the heart at multi‐physical scales including cellular and tissue levels. We also conducted some simulations to demonstrate the application of the virtual heart to assess the pro‐arrhythmic effects of cisapride and amiodarone. Using the model we investigated the mechanisms responsible for the differences between the two drugs on pro‐arrhythmogenesis, even though both prolong the QT interval of ECGs. Several challenges for further development of a virtual heart as a platform for screening drug cardiotoxicity are discussed.Linked ArticlesThis article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

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“…It has been shown that drugs with similar binding affinity but different binding kinetics can have diverse effects[3, 149, 150]. The most commonly used metric for drug blockade is IC 50 , but it provides an average measure of drug potency to supress ion currents without any mechanistic insights.…”

Section: Towards Md-based Kinetic Models For Ion Channels Gating mentioning

confidence: 99%

Computational membrane biophysics: From ion channel interactions with drugs to cellular function

Miranda

Ngo

Perissinotti

et al. 2017

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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The rapid development of experimental and computational techniques has changed fundamentally our understanding of cellular-membrane transport. The advent of powerful computers and refined force-fields for proteins, ions, and lipids has expanded the applicability of Molecular Dynamics (MD) simulations. A myriad of cellular responses is modulated through the binding of endogenous and exogenous ligands (e.g. neurotransmitters and drugs, respectively) to ion channels. Deciphering the thermodynamics and kinetics of the ligand binding processes to these membrane proteins is at the heart of modern drug development. The ever-increasing computational power has already provided insightful data on the thermodynamics and kinetics of drug-target interactions, free energies of solvation, and partitioning into lipid bilayers for drugs. This review aims to provide a brief summary about modeling approaches to map out crucial binding pathways with intermediate conformations and free-energy surfaces for drug-ion channel binding mechanisms that are responsible for multiple effects on cellular functions. We will discuss post-processing analysis of simulation-generated data, which are then transformed to kinetic models to better understand the molecular underpinning of the experimental observables under the influence of drugs or mutations in ion channels. This review highlights crucial mathematical frameworks and perspectives on bridging different well-established computational techniques to connect the dynamics and timescales from all-atom MD and free energy simulations of ion channels to the physiology of action potentials in cellular models.

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Kinetics of Drug Interaction with the K_v11.1 Potassium Channel

Cited by 23 publications

References 30 publications

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

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

The virtual heart as a platform for screening drug cardiotoxicity

Computational membrane biophysics: From ion channel interactions with drugs to cellular function

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Kinetics of Drug Interaction with the Kv11.1 Potassium Channel

Cited by 23 publications

References 30 publications

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

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

The virtual heart as a platform for screening drug cardiotoxicity

Computational membrane biophysics: From ion channel interactions with drugs to cellular function

Contact Info

Product

Resources

About

Kinetics of Drug Interaction with the K_v11.1 Potassium Channel

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

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