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

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

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.

• Jezik: Angleški jezik
• Ključne besede: cancer, Eag1, hERG, K$_V$10.1 inhibitors, molecular dynamics, pharmacophore
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2021
• Št. strani: 24 str.
• Številčenje: Vol. 22, iss. 16, art. 8999
• PID: 20.500.12556/RUL-136040
• UDK: 615.4:54:616-006
• ISSN pri članku: 1422-0067
• DOI: 10.3390/ijms22168999
• COBISS.SI-ID: 73744899
• Datum objave v RUL: 08.04.2022

Gradivo je del revije

• Naslov: International journal of molecular sciences
• Skrajšan naslov: Int. j. mol. sci.
• Založnik: MDPI
• ISSN: 1422-0067
• COBISS.SI-ID: 2779162

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 20.08.2021

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: zaviralci kalijevih kanalčkov, molekularna dinamika, farmakofor, rak, farmacevtska kemija