Key result
In silico models accurately predict hERG block and drug-induced QT prolongation risk.
Why the study?
Consideration of QT interval prolongation and the risk for torsade de pointes is critical in evaluating new bioactive agents, with recent advances in understanding the I(Kr) channel and risk factors for QT prolongation.
Answers are grounded in this paper and cite their sources.
Supports refinement of in silico hERG screening in drug development; leaves open rigorous clinical validation before routine use.
Consideration of QT interval prolongation and the risk for developing torsade de pointes is a critical issue in the evaluation of new bioactive agents. Over the past several years, there has been a dramatic increase in understanding the I(Kr) channel and its role in the duration of the action potential and cardiac repolarization. Furthermore, a variety of factors and situations have been identified that can increase the risk of QT interval prolongation. In this brief summary, an overview of the hERG channel and QT prolongation will be presented. The basic electro-physiology of the heart, the related action potentials, and pre-clinical assays is reviewed. Further, an introduction to the current status of in silico efforts in predicting potential hERG blockers is discussed. Lastly, the strengths and weaknesses of each modeling method is presented along with insight to the appropriate use of each model.
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Jalaie et al. (2005) conducted a review in QT interval prolongation and torsade de pointes. This review summarizes the basic electrophysiology of the hERG channel, mechanisms of QT prolongation, and the current status and utility of in silico models for predicting potential hERG blockers.
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