Drugs inhibiting slow delayed rectifying potassium current (IKs) - literature data analysis and predictive model development

presentation · 6 years ago
by Sebastian Polak, Aleksander Mendyk, Barbara Wiƛniowska, Anna Glinka, Kamil Fijorek (Jagiellonian University)
MarvinSketch
The excitable cell membranes contain the ion channels, what allow the ions passage through the specific pores by a passive process. Dynamic equilibrium formed on the border can be harmed and skewed by the xenobiotics and the mechanism lies in the ionic currents disruption. The assessment of the inhibition of the IKr current formed by the hERG channels is considered as the main target during the drug development process. Although there are other ionic currents for which the drug triggered modification can either potentiate or mask hERG channel blockade. In the current research information describing the results of the in vitro studies investigating the chemicals-IKs current interactions was developed. Based on the publicly available data we were able to collect data for 145 records. The final list of publications consists of 64 positions and refers to 107 different molecules connected with the IKs current inhibition with at least one IC50 value measured. Ultimately, 98 of the IC50 values expressed as the absolute values were gathered. 36 elements were expressed as the relative values. For 11 remaining cases the inhibition was not clearly expressed. Based on the collected data the predictive models for the IC50 estimation was developed with use of various algorithms. The extended QSAR methodology was applied and the in vitro research settings were included as the independent variables apart from the physico-chemical descriptors calculated with use of the Marvin Calculator Plugins. The RMSE and NRMSE values for the best model (expert system based on two independent artificial neural networks) were 0.86 and 14.04% respectively. The above mentioned model was further build-in to the ToxComp system - ToxIVIVE tool specialized in the drugs cardiotoxicity assessment.

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