In Vitro and In Silico Risk Assessment in Acquired Long QT Syndrome: The Devil Is in the Details.

William Lee,Jamie I Vandenberg,Adam P Hill,Monique J Windley

doi:10.3389/fphys.2017.00934

William Lee, Jamie I Vandenberg + Show 2 more

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https://doi.org/10.3389/fphys.2017.00934

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Abstract

Acquired long QT syndrome, mostly as a result of drug block of the Kv11. 1 potassium channel in the heart, is characterized by delayed cardiac myocyte repolarization, prolongation of the T interval on the ECG, syncope and sudden cardiac death due to the polymorphic ventricular arrhythmia Torsade de Pointes (TdP). In recent years, efforts are underway through the Comprehensive in vitro proarrhythmic assay (CiPA) initiative, to develop better tests for this drug induced arrhythmia based in part on in silico simulations of pharmacological disruption of repolarization. However, drug binding to Kv11.1 is more complex than a simple binary molecular reaction, meaning simple steady state measures of potency are poor surrogates for risk. As a result, there is a plethora of mechanistic detail describing the drug/Kv11.1 interaction—such as drug binding kinetics, state preference, temperature dependence and trapping—that needs to be considered when developing in silico models for risk prediction. In addition to this, other factors, such as multichannel pharmacological profile and the nature of the ventricular cell models used in simulations also need to be considered in the search for the optimum in silico approach. Here we consider how much of mechanistic detail needs to be included for in silico models to accurately predict risk and further, how much of this detail can be retrieved from protocols that are practical to implement in high throughout screens as part of next generation of preclinical in silico drug screening approaches?

Highlights

In the past 20 years, a range of structurally unrelated drugs, including antihistamines, antibiotics and antipsychotics, have been withdrawn from the market due to adverse effects on cardiac repolarization - so called acquired long QT syndrome. aLQTS is characterized by prolongation and sometimes morphological deformation of QT segments on the 12-lead electrocardiogram (ECG), syncope and sudden cardiac death due to the polymorphic ventricular arrhythmia Torsade de Pointes (TdP)
Discrimination between drugs with low, medium and high risk of proarrhythmia using the metric ability of the “cqInward” is incrementally improved when descriptions of trapping and kinetics are included in simulation as compared to simple IC50 measures of drug potency (Li et al, 2017; Figure 2)
It is likely that the recent advent of high resolution structures of Kv11.1 (Wang and MacKinnon, 2017) and the potential this presents to generate more structures of drugs interacting with inactivation deficient Kv11.1 channels, will allow more accurate molecular dynamic simulations to probe these questions around state-dependent drug binding in more detail

Summary

Introduction

In the past 20 years, a range of structurally unrelated drugs, including antihistamines, antibiotics and antipsychotics, have been withdrawn from the market due to adverse effects on cardiac repolarization - so called acquired long QT syndrome (aLQTS). aLQTS is characterized by prolongation and sometimes morphological deformation of QT segments on the 12-lead electrocardiogram (ECG), syncope and sudden cardiac death due to the polymorphic ventricular arrhythmia Torsade de Pointes (TdP). The inclusion of drug binding kinetics in in silico simulations has been demonstrated to significantly alter predictions of cardiac action potential prolongation (Di Veroli et al, 2014; Lee et al, 2016).

Results

Conclusion