Molecular dynamics-derived pharmacophore model explaining the nonselective aspect of K$_V$10.1 pore blockers

The K$_V$10.1 voltage-gated potassium channel is highly expressed in 70% of tumors, and thus represents a promising target for anticancer drug discovery. However, only a few ligands are known to inhibit K$_V$10.1, and almost all also inhibit the very similar cardiac hERG channel, which can lead to undesirable side-effects. In the absence of the structure of the K$_V$10.1–inhibitor complex, there remains the need for new strategies to identify selective K$_V$10.1 inhibitors and to understand the binding modes of the known K$_V$10.1 inhibitors. To investigate these binding modes in the central cavity of K$_V$10.1, a unique approach was used that allows derivation and analysis of ligand–protein interactions from molecular dynamics trajectories through pharmacophore modeling. The final molecular dynamics-derived structure-based pharmacophore model for the simulated K$_V$10.1–ligand complexes describes the necessary pharmacophore features for K$_V$10.1 inhibition and is highly similar to the previously reported ligand-based hERG pharmacophore model used to explain the nonselectivity of K$_V$10.1 pore blockers. Moreover, analysis of the molecular dynamics trajectories revealed disruption of the π–π network of aromatic residues F359, Y464, and F468 of K$_V$10.1, which has been reported to be important for binding of various ligands for both K$_V$10.1 and hERG channels. These data indicate that targeting the K$_V$10.1 channel pore is also likely to result in undesired hERG inhibition, and other potential binding sites should be explored to develop true K$_V$10.1-selective inhibitors as new anticancer agents