Calculations of the binding free energies of the Comprehensive Proarrhythmia Assay (CiPA) reference drugs to cardiac ion channels.

The evaluation of the inhibitory activities of drugs on multiple cardiac ion channels is required for the accurate assessment of proarrhythmic risks. Moreover, the prediction of such inhibitory activities of drugs on cardiac channels can improve the efficiency of the drug-development process. Here, we performed molecular docking simulations to predict the complex structures of 25 reference drugs that were proposed by the Comprehensive Proarrhythmia Assay consortium using two cardiac ion channels, the human ether-a-go-go-related gene (hERG) potassium channel and human Na1.5 (hNa1.5) sodium channel, with experimentally available structures. The absolute binding free energy (Δ) values of the predicted structures were calculated by a molecular dynamics-based method and compared with the experimental half-maximal inhibitory concentration (IC) data. Furthermore, the regression analysis between the calculated values and negative of the common logarithm of the experimental IC values (pIC) revealed that the calculated values of four and ten drugs deviated significantly from the regression lines of the hERG and hNa1.5 channels, respectively. We reconsidered the docking poses and protonation states of the drugs based on the experimental data and recalculated their Δ values. Finally, the calculated Δ values of 24 and 19 drugs correlated with their experimental pIC values (coefficients of determination=0.791 and 0.613 for the hERG and hNa1.5 channels, respectively). Thus, the regression analysis between the calculated Δ and experimental IC data ensured the realization of an increased number of reliable complex structures.