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

Toplak, Žan (author), Merzel, Franci (author), Pardo, Luis A. (author), Peterlin-Mašič, Lucija (author), Tomašič, Tihomir (author)

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.

• Language: English
• Keywords: cancer, Eag1, hERG, K$_V$10.1 inhibitors, molecular dynamics, pharmacophore
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 24 str.
• Numbering: Vol. 22, iss. 16, art. 8999
• PID: 20.500.12556/RUL-136040
• UDC: 615.4:54:616-006
• ISSN on article: 1422-0067
• DOI: 10.3390/ijms22168999
• COBISS.SI-ID: 73744899
• Publication date in RUL: 08.04.2022

Record is a part of a journal

• Title: International journal of molecular sciences
• Shortened title: Int. j. mol. sci.
• Publisher: MDPI
• ISSN: 1422-0067
• COBISS.SI-ID: 2779162

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 20.08.2021

Secondary language

• Language: Slovenian
• Keywords: zaviralci kalijevih kanalčkov, molekularna dinamika, farmakofor, rak, farmacevtska kemija