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.