A temperature-dependent in silico model of the human ether-�-go-go-related (hERG) gene channel

Zhihua Li, Sara Dutta, Jiansong Sheng, Phu N. Tran, Wendy Wu, Thomas Colatsky

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Introduction Current regulatory guidelines for assessing the risk of QT prolongation include in vitro assays assessing drug effects on the human ether-�-go-go-related (hERG; also known as Kv11.1) channel expressed in cell lines. These assays are typically conducted at room temperature to promote the ease and stability of recording hERG currents. However, the new Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm proposes to use an in silico model of the human ventricular myocyte to assess risk, requiring as input hERG channel pharmacology data obtained at physiological temperatures. To accommodate current industry safety pharmacology practices for measuring hERG channel activity, an in silico model of hERG channel that allows for the extrapolation of hERG assay data across different temperatures is desired. Because temperature may have an effect on both channel gating and drug binding rate, such models may need to have two components: a base model dealing with temperature-dependent gating changes without drug, and a pharmacodynamic component simulating temperature-dependent drug binding kinetics. As a first step, a base mode that can capture temperature effects on hERG channel gating without drug is needed. Methods and results To meet this need for a temperature-dependent base model, a Markov model of the hERG channel with state transition rates explicitly dependent on temperature was developed and calibrated using data from a variety of published experiments conducted over a range of temperatures. The model was able to reproduce observed temperature-dependent changes in key channel gating properties and also to predict the results obtained in independent sets of new experiments. Discussion This new temperature-sensitive model of hERG gating represents an attempt to improve the predictivity of safety pharmacology testing by enabling the translation of room temperature hERG assay data to more physiological conditions. With further development, this model can be incorporated into the CiPA paradigm and also be used as a tool for developing insights into the thermodynamics of hERG channel gating mechanisms and the temperature-dependence of hERG channel block by drugs.

Original languageEnglish (US)
Pages (from-to)233-239
Number of pages7
JournalJournal of Pharmacological and Toxicological Methods
Volume81
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

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Computer Simulation
Ether
Genes
Temperature
Assays
Pharmaceutical Preparations
Pharmacology
Safety testing
Pharmacodynamics
Safety
Extrapolation
Thermal effects
Thermodynamics
Muscle Cells
Industry
Experiments
Cells
Pharmacokinetics
Guidelines

Keywords

  • CiPA
  • hERG
  • Kv11.1
  • Markov model
  • Methods
  • Temperature

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

A temperature-dependent in silico model of the human ether-�-go-go-related (hERG) gene channel. / Li, Zhihua; Dutta, Sara; Sheng, Jiansong; Tran, Phu N.; Wu, Wendy; Colatsky, Thomas.

In: Journal of Pharmacological and Toxicological Methods, Vol. 81, 01.09.2016, p. 233-239.

Research output: Contribution to journalArticle

Li, Zhihua ; Dutta, Sara ; Sheng, Jiansong ; Tran, Phu N. ; Wu, Wendy ; Colatsky, Thomas. / A temperature-dependent in silico model of the human ether-�-go-go-related (hERG) gene channel. In: Journal of Pharmacological and Toxicological Methods. 2016 ; Vol. 81. pp. 233-239.
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AU - Wu, Wendy

AU - Colatsky, Thomas

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N2 - Introduction Current regulatory guidelines for assessing the risk of QT prolongation include in vitro assays assessing drug effects on the human ether-�-go-go-related (hERG; also known as Kv11.1) channel expressed in cell lines. These assays are typically conducted at room temperature to promote the ease and stability of recording hERG currents. However, the new Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm proposes to use an in silico model of the human ventricular myocyte to assess risk, requiring as input hERG channel pharmacology data obtained at physiological temperatures. To accommodate current industry safety pharmacology practices for measuring hERG channel activity, an in silico model of hERG channel that allows for the extrapolation of hERG assay data across different temperatures is desired. Because temperature may have an effect on both channel gating and drug binding rate, such models may need to have two components: a base model dealing with temperature-dependent gating changes without drug, and a pharmacodynamic component simulating temperature-dependent drug binding kinetics. As a first step, a base mode that can capture temperature effects on hERG channel gating without drug is needed. Methods and results To meet this need for a temperature-dependent base model, a Markov model of the hERG channel with state transition rates explicitly dependent on temperature was developed and calibrated using data from a variety of published experiments conducted over a range of temperatures. The model was able to reproduce observed temperature-dependent changes in key channel gating properties and also to predict the results obtained in independent sets of new experiments. Discussion This new temperature-sensitive model of hERG gating represents an attempt to improve the predictivity of safety pharmacology testing by enabling the translation of room temperature hERG assay data to more physiological conditions. With further development, this model can be incorporated into the CiPA paradigm and also be used as a tool for developing insights into the thermodynamics of hERG channel gating mechanisms and the temperature-dependence of hERG channel block by drugs.

AB - Introduction Current regulatory guidelines for assessing the risk of QT prolongation include in vitro assays assessing drug effects on the human ether-�-go-go-related (hERG; also known as Kv11.1) channel expressed in cell lines. These assays are typically conducted at room temperature to promote the ease and stability of recording hERG currents. However, the new Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm proposes to use an in silico model of the human ventricular myocyte to assess risk, requiring as input hERG channel pharmacology data obtained at physiological temperatures. To accommodate current industry safety pharmacology practices for measuring hERG channel activity, an in silico model of hERG channel that allows for the extrapolation of hERG assay data across different temperatures is desired. Because temperature may have an effect on both channel gating and drug binding rate, such models may need to have two components: a base model dealing with temperature-dependent gating changes without drug, and a pharmacodynamic component simulating temperature-dependent drug binding kinetics. As a first step, a base mode that can capture temperature effects on hERG channel gating without drug is needed. Methods and results To meet this need for a temperature-dependent base model, a Markov model of the hERG channel with state transition rates explicitly dependent on temperature was developed and calibrated using data from a variety of published experiments conducted over a range of temperatures. The model was able to reproduce observed temperature-dependent changes in key channel gating properties and also to predict the results obtained in independent sets of new experiments. Discussion This new temperature-sensitive model of hERG gating represents an attempt to improve the predictivity of safety pharmacology testing by enabling the translation of room temperature hERG assay data to more physiological conditions. With further development, this model can be incorporated into the CiPA paradigm and also be used as a tool for developing insights into the thermodynamics of hERG channel gating mechanisms and the temperature-dependence of hERG channel block by drugs.

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