Lee, William and Windley, Monique J and Vandenberg, Jamie I and Hill, Adam P (2017) In Vitro and In Silico Risk Assessment in Acquired Long QT Syndrome: The Devil Is in the Details. Frontiers in Physiology, 8. p. 934. ISSN 1664-042X (OA)
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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?
| Item Type: | Article |
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| Additional Information: | This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 12 Dec 2017 01:29 |
| Last Modified: | 12 Dec 2017 01:29 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/673 |
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