A Multiscale Simulation System for the Prediction of Drug-Induced Cardiotoxicity

Abstract

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.

In silico assessment of drug safety in human heart applied to late sodium current blockers

“…Other computational studies have assessed the effects of I Ks and/or I Kr blockers on several biomarkers for arrhythmic risk as a proof of concept in the preclinical phase of development of drugs. 26,27,67 Our work complements and extends these approaches. We have evaluated for the first time the safety of drugs with different ratios of I NaL /I Kr block, using a recent and very detailed human AP model.…”

“…[22][23][24] Within the past 3 y, computer simulations have been employed in drug development programs with the goal of assessing in silico risk for drug-induced cardiac arrhythmia. [25][26][27][28] However, only Mirams et al 25 and Sarkar et al 29 utilized human AP models, in addition to models of the rabbit and dog ventricular APs.…”

hERG K+Channels: Structure, Function, and Clinical Significance

“…To this end, a recent study used 3D-QSAR and docking simulations to predict block of both I Kr (Kv11.1) and I Ks (Kv7.1), before incorporating this information into a guinea pig ventricular tissue model (455). This integrated model then allowed the simulation of individual action potentials, pseudo-ECGs, and 2D-maps of action potential propagation through simulated ventricular tissue.…”

Legacy data sharing to improve drug safety assessment: the eTOX project

“…), in which innovative modeling strategies have been applied (1,2). The extraction and integration of information from public sources for model development has been facilitated by an ad hoc tool (Collector), which operates on top of the IMI Open PHACTS data infrastructure.…”