In silico Safety Pharmacology

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PROJECT SUMMARY: A major factor plaguing drug development is that there is no preclinical drug screen that can accurately predict unintended drug induced cardiac arrhythmias. The current approaches rely on substitute markers such as QT interval prolongation on the ECG. Unfortunately, QT prolongation is neither specific nor sensitive to indicate likelihood of arrhythmias. There is an urgent need to identify a new approach that can predict actual proarrhythmia rather than surrogate indicators. Mathematical modeling and simulation constitutes one of the most promising methodologies to reveal fundamental biological principles and mechanisms, model effects of interactions between system components and predict emergent drug effects. Thus, we propose the development of a novel multiscale approach based on drug-channel structural interactions and kinetics intended to predict drug induced cardiotoxicity in the context of: 1) preclinical drug screening, 2) drug rehabilitation, and 3) prediction of the intersection of drug effects and coexistent risk factors. Our underlying hypothesis is that the fundamental mode of drug interaction derived from each drug’s unique structure activity relationship determines the resultant effects on cardiac electrical activity in cells and tissue. By capturing these complex drug channel interactions in a model, we expect to be able to predict drug safety or electro-toxicity in the heart. We have brought together an expert team to assemble and test a new multiscale model framework that connects detailed mathematical models to predict atomic scale interactions of drugs on the promiscuous hERG potassium channel to functional scale predictions at the level of the channel, cell and tissue. Predictions from the atomic structure simulations will be used to inform the kinetic parameters of models that capture the complex dynamical interactions of drugs and ion channels. The computational components will then be studied in predictive models at the channel, cell and tissue scales to expose fundamental mechanisms and complex interactions underlying emergent behaviors. Experiments in mammalian cells and tissues will be undertaken to validate model predictions. Drug properties will be perturbed in models to rehabilitate dangerous drugs and reduce their potential toxicity. The multiscale model for prediction of cardiopharmacology that we will develop in this application will be applied to projects demonstrating its usefulness for efficacy or toxicity of drug treatments in the complex physiological system of the heart.