J Chem Inf Model - A multiscale simulation system for the prediction of drug-induced cardiotoxicity.


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The preclinical assessment of drug-induced ventricular arrhythmia, a major concern for regulators, is typically based on experimental or computational models focused on the potassium channel hERG (human ether-a-go-go-related gene, K(v)11.1). Even if the role of this ion channel in the ventricular repolarization is of critical importance, the complexity of the events involved make the cardiac safety assessment based only on hERG has a high risk of producing either false positive or negative results. We introduce a multiscale simulation system aiming to produce a better cardiotoxicity assessment. At the molecular scale, the proposed system uses a combination of docking simulations on two potassium channels, hERG and KCNQ1, plus three-dimensional quantitative structure-activity relationship modeling for predicting how the tested compound will block the potassium currents IK(r) and IK(s). The obtained results have been introduced in electrophysiological models of the cardiomyocytes and the ventricular tissue, allowing the direct prediction of the drug effects on electrocardiogram simulations. The usefulness of the whole method is illustrated by predicting the cardiotoxic effect of several compounds, including some examples in which classic hERG-based models produce false positive or negative results, yielding correct predictions for all of them. These results can be considered a proof of concept, suggesting that multiscale prediction systems can be suitable for being used for preliminary screening in lead discovery, before the compound is physically available, or in early preclinical development when they can be fed with experimentally obtained data.

Resumo Limpo

preclin assess druginduc ventricular arrhythmia major concern regul typic base experiment comput model focus potassium channel herg human etheragogorel gene kv even role ion channel ventricular repolar critic import complex event involv make cardiac safeti assess base herg high risk produc either fals posit negat result introduc multiscal simul system aim produc better cardiotox assess molecular scale propos system use combin dock simul two potassium channel herg kcnq plus threedimension quantit structureact relationship model predict test compound will block potassium current ikr ik obtain result introduc electrophysiolog model cardiomyocyt ventricular tissu allow direct predict drug effect electrocardiogram simul use whole method illustr predict cardiotox effect sever compound includ exampl classic hergbas model produc fals posit negat result yield correct predict result can consid proof concept suggest multiscal predict system can suitabl use preliminari screen lead discoveri compound physic avail earli preclin develop can fed experiment obtain data

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