20.500.12556/RUL-136040 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$10.1-selective inhibitors as new anticancer agents. cancer Eag1 hERG K$_V$10.1 inhibitors molecular dynamics pharmacophore zaviralci kalijevih kanalčkov molekularna dinamika farmakofor rak farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2022-04-08 10:51:20 2022-04-08 10:51:27 2022-09-15 04:13:18 0000-00-00 00:00:00 2021 0 0 24 str. iss. 16, art. 8999 Vol. 22 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54:616-006 1422-0067 10.3390/ijms22168999 73744899 RAZ_Toplak_Zan_2021.pdf RAZ_Toplak_Zan_2021.pdf 1 F9305A44099CECF44B19C17785E2A928 a1724baf43aa038ca471042d44f9c5021edf0ce876eb77093ce4407cecdedff3 5cc51c75-b719-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155472 https://www.mdpi.com/1422-0067/22/16/8999 1 08de9f51-b719-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155471 Fakulteta za farmacijo 0 0 0