Combining structure- and ligand-based approaches for studies of interactions between different conformations of the hERG K+ channel pore and known ligands

•Four conformational states of the hERG K+ channel are built by using Modeller.•A dataset of 59 compounds is docked into the four 3D-models by using Autodock.•Docking-based and PaDEL-calculated descriptors are used for four QSAR tasks.•The intermediate conformation showed the best fitting with experimental data.

Drug-induced insurgence of cardiotoxic effects signaled by the prolongation of the QT interval in the electrocardiogram, has the potential to evolve into a characteristic arrhythmic event named Torsade de Pointes (TdP). Although several different mechanisms can theoretically lead to prolonged QT interval, most of drugs showing this side effect, prolong the cardiac repolarization time through the inhibition of the rapid component of the delayed repolarizing current (IKr) which in humans is carried by a K+ channel protein encoded by hERG. In this study, four 3D-models, representing different conformational states of hERG K+ channel, were built by a homology-based technique. A dataset of 59 compounds was collected from the literature and rationally selected according to the availability of IC50 values derived from whole-cell patch clamp performed at 37 °C on HEK cells.Molecular docking was carried out on each one of the four conformations of the channel, hundreds of docking-based molecular descriptors were obtained and used, together with other 2D and 3D molecular descriptors, to develop QSAR models. The statistical parameters describing the accordance between predicted and experimental data and the interpretation of the QSAR models enabled us to assess the reliability of the four 3D-models of the channel pore, thus allowing to look in more depth at binding modes and key features of the interactions occurring between the hERG K+ channel and ligands endowed of blocking activity.

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