LIDER detailed project description
System covers four modules which are presented and described below.
MODULE 1 – hERG – tool for predicting hERG channel inhibition potential based on the physico-chemical descriptors of chemical entities. It is planned to test various descriptors beginning from easily derived or calculated even at the very early stage of the drug development like logP, pKa, HBD to more sophisticated describing 2D and 3D structure of the substance (i.e. chemical fingerprints). The models output is expressed as the IC50 value (drug concentration given 50% inhibition of the potassium ions flow through the channel). This value is primarily measured during the laboratory research based on the in vitro cell lines with use of various techniques (Patch Clamp is the standard one). The final platform user will be able to use both source of data for the hERG IC50 values either derived from the laboratory studies (different cell lines – HEK293, CHO, XO) or calculated with use of the build-in in silico calculators. Best developed algorithms will be implemented as well as chosen algorithms derived from the literature.
MODULE 2 – IONS – to assess the influence of the compound undergoing testing procedure on the remaining potassium (IKs, Ito) and other ion channels taking part in the electrophysiological activity of the heart ventricular cell membrane (Na, Ca). Analogically the platform can be fed with the IC50 values from both sources – in vitro studies and in silico prediction.
MODULE 3 – HEART VENTRICULAR CELL MODELS – contains various available in the literature mathematical models of the human heart ventricular cell. Models parameters cover ionic currents which can be modified according to the MODULE 1 and MODULE 2 results and allows simulating drug influence on the heart action potential. Some of the parameters are describe physiological factor (i.e. cell volume and surface) and are sources of the inter-individual variability. MODULE 3 contains also databases of the physiological parameters distribution in the population and sampling algorithm which are used for the virtual population ad hoc development during the simulation.
MODULE 4 – PBPK – external module which allows to connect and directly use the results of the IVIVE software predicting the drug time-concentration changes in plasma and tissues including heart tissue.