SP1 MULTI-SCALE MODELLING
Within HeCaToS SP1 five types of modelling components will be vertically integrated to explicitly link drug delivery, uptake and protein interactions to cellular and whole organ response. Molecular dynamics simulations will be performed in WP1 to estimate toxicant transfer rates across the membrane and equilibrium constants, binding and unbinding rates proteins in the mitochondria and cell membrane. Critical pathways associated with cardiac toxicity will be identified and modelled in WP2. Estimated drug kinetics and toxicity pathways will be combined with the predicted extracellular drug levels from physiologically based pharmo-kinetic models, developed in WP3, to predict the effect of specific compounds on cardiac and liver protein function. In WP4 the predicted drug-protein interactions will be introduced into cellular models to link drug induced changes in protein function to alterations in cellular physiology. Changes in cellular function will then be introduced into organ scale models in WP4 to predict the effect of these drugs at the scale of clinical diagnostics.