VPH NoE Exemplar Projects and the VPH ToolKit - 4. Multi-scale simulation and prediction of the drug safety problems related with hERG PDF | Print | E-mail

4. Multi-scale simulation and prediction of the drug safety problems related with hERG

Lead: IMIM, This e-mail address is being protected from spambots. You need JavaScript enabled to view it

URL: http://multiscalelab.org/VPH

An important field of application of the VPH concept is the drug development process since multi-scale simulations can be extremely useful for the understanding of the physiological mechanisms related with the therapeutic efficacy of the drugs, as well as with their adverse events (drug safety problems). In order to get useful in-silico predictions of the efficacy and safety of drugs, we require computational models that have to be sensitive to the differential molecular characteristics of the drugs, which, on the other hand, have to be coupled with models simulating the biological system or organ in which the therapeutic effectiveness or adverse events are observed. The hERG-related cardiac adverse effects of drugs are a paradigmatic example of this approach. Although other potential targets for cardiac adverse effects exist, the vast majority of drugs associated with pathological prolongations of the QT segment of the electrocardiogram are known to interact with the hERG potassium channel. The differential interaction of series of drugs under development with the hERG potassium channel can be simulated at the molecular scale by means of atomistic simulations coupled to drug discovery tools based on quantitative structure activity relationships. In this way one will be able to obtain quantitative predictions of electrophysiological parameters of each drug that could be used in both mesoscopic simulations dealing with macromolecular behaviour of the channels and, more importantly, macroscopic electromechanical simulations of the hearth with the aim of predicting the change in the QT segment generated by the drugs under study.

This approach will be based on tools developed in several projects that are focused on the multiscale processes modelling and their computational implementation (PS3Grid and EC-STREP QosCosGrid) as well as on the translational research aspects of such a multilevel problem (EC-STREP BioBridge). This seed EP will aim at integrating existing software tools dealing with the several levels of complexity of the QT elongation. The expected outcome of the next step will be the standarisation of formats for easy integration of simulation scales and the computational implementation of the different levels of detail.