Abstract
The KV10.1 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 KV10.1, 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 KV10.1–inhibitor complex, there remains the need for new strategies to identify selective KV10.1 inhibitors and to understand the binding modes of the known KV10.1 inhibitors. To investigate these binding modes in the central cavity of KV10.1, 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 KV10.1–ligand complexes describes the necessary pharmacophore features for KV10.1 inhibition and is highly similar to the previously reported ligand-based hERG pharmacophore model used to explain the nonselectivity of KV10.1 pore blockers. Moreover, analysis of the molecular dynamics trajectories revealed disruption of the π–π network of aromatic residues F359, Y464, and F468 of KV10.1, which has been reported to be important for binding of various ligands for both KV10.1 and hERG channels. These data indicate that targeting the KV10.1 channel pore is also likely to result in undesired hERG inhibition, and other potential binding sites should be explored to develop true KV10.1-selective inhibitors as new anticancer agents.
Highlights
KV 10.1 (Eag1) is a voltage-gated potassium channel of the ‘ether-à-go-go’ channel family
The creation of the common structure-based pharmacophore model for KV 10.1 inhibitors binding to the channel pore allowed us to compare it with the known hERG ligand-based pharmacophore models and to assess the potential for targeting the KV 10.1 channel pore for the development of KV 10.1-selective anticancer agents
We used a combination of several molecular modeling techniques to analyze the binding mode of astemizole, clofilium, imipramine, MK-499, and quinidine in the pore of KV 10.1, which is a promising target for anticancer drug development as it is expressed in more than 70% of tumors
Summary
KV 10.1 (Eag1) is a voltage-gated potassium channel of the ‘ether-à-go-go’ channel family. Within this family, the hERG channel (eag-related gene, KV 11.1) is known to be responsible for increased risk of malignant cardiac arrhythmia, which can lead to sudden cardiac death [1,2,3]. KV 10.1 is almost not detectable outside the human central nervous system, except in many different tumors, where its expression is dysregulated. The high expression of KV 10.1 in 70% of various tumors and cancers make this channel a potential cancer marker and target for anticancer drugs [6]. KV 10.1 is a homotetramer of four identical subunits, each of which consists of the intracellular N-terminal Per-Arnt-Sim (PAS) domain, and the C-terminal cyclic nucleotidebinding domain and transmembrane portion, which has six α-helical segments (S1–S6)
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