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Computational Identification of Novel Kir6 Channel Inhibitors

KATP channels consist of four Kir6.x pore–forming subunits and four regulatory sulfonylurea receptor (SUR) subunits. These channels couple the metabolic state of the cell to membrane excitability and play a key role in physiological processes such as insulin secretion in the pancreas, protection of...

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Autores principales: Chen, Xingyu, Garon, Arthur, Wieder, Marcus, Houtman, Marien J. C., Zangerl-Plessl, Eva-Maria, Langer, Thierry, van der Heyden, Marcel A. G., Stary-Weinzinger, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543810/
https://www.ncbi.nlm.nih.gov/pubmed/31178728
http://dx.doi.org/10.3389/fphar.2019.00549
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author Chen, Xingyu
Garon, Arthur
Wieder, Marcus
Houtman, Marien J. C.
Zangerl-Plessl, Eva-Maria
Langer, Thierry
van der Heyden, Marcel A. G.
Stary-Weinzinger, Anna
author_facet Chen, Xingyu
Garon, Arthur
Wieder, Marcus
Houtman, Marien J. C.
Zangerl-Plessl, Eva-Maria
Langer, Thierry
van der Heyden, Marcel A. G.
Stary-Weinzinger, Anna
author_sort Chen, Xingyu
collection PubMed
description KATP channels consist of four Kir6.x pore–forming subunits and four regulatory sulfonylurea receptor (SUR) subunits. These channels couple the metabolic state of the cell to membrane excitability and play a key role in physiological processes such as insulin secretion in the pancreas, protection of cardiac muscle during ischemia and hypoxic vasodilation of arterial smooth muscle cells. Abnormal channel function resulting from inherited gain or loss-of-function mutations in either the Kir6.x and/or SUR subunits are associated with severe diseases such as neonatal diabetes, congenital hyperinsulinism, or Cantú syndrome (CS). CS is an ultra-rare genetic autosomal dominant disorder, caused by dominant gain-of-function mutations in SUR2A or Kir6.1 subunits. No specific pharmacotherapeutic treatment options are currently available for CS. Kir6 specific inhibitors could be beneficial for the development of novel drug therapies for CS, particular for mutations, which lack high affinity for sulfonylurea inhibitor glibenclamide. By applying a combination of computational methods including atomistic MD simulations, free energy calculations and pharmacophore modeling, we identified several novel Kir6.1 inhibitors, which might be possible candidates for drug repurposing. The in silico predictions were confirmed using inside/out patch-clamp analysis. Importantly, Cantú mutation C166S in Kir6.2 (equivalent to C176S in Kir6.1) and S1020P in SUR2A, retained high affinity toward the novel inhibitors. Summarizing, the inhibitors identified in this study might provide a starting point toward developing novel therapies for Cantú disease.
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spelling pubmed-65438102019-06-07 Computational Identification of Novel Kir6 Channel Inhibitors Chen, Xingyu Garon, Arthur Wieder, Marcus Houtman, Marien J. C. Zangerl-Plessl, Eva-Maria Langer, Thierry van der Heyden, Marcel A. G. Stary-Weinzinger, Anna Front Pharmacol Pharmacology KATP channels consist of four Kir6.x pore–forming subunits and four regulatory sulfonylurea receptor (SUR) subunits. These channels couple the metabolic state of the cell to membrane excitability and play a key role in physiological processes such as insulin secretion in the pancreas, protection of cardiac muscle during ischemia and hypoxic vasodilation of arterial smooth muscle cells. Abnormal channel function resulting from inherited gain or loss-of-function mutations in either the Kir6.x and/or SUR subunits are associated with severe diseases such as neonatal diabetes, congenital hyperinsulinism, or Cantú syndrome (CS). CS is an ultra-rare genetic autosomal dominant disorder, caused by dominant gain-of-function mutations in SUR2A or Kir6.1 subunits. No specific pharmacotherapeutic treatment options are currently available for CS. Kir6 specific inhibitors could be beneficial for the development of novel drug therapies for CS, particular for mutations, which lack high affinity for sulfonylurea inhibitor glibenclamide. By applying a combination of computational methods including atomistic MD simulations, free energy calculations and pharmacophore modeling, we identified several novel Kir6.1 inhibitors, which might be possible candidates for drug repurposing. The in silico predictions were confirmed using inside/out patch-clamp analysis. Importantly, Cantú mutation C166S in Kir6.2 (equivalent to C176S in Kir6.1) and S1020P in SUR2A, retained high affinity toward the novel inhibitors. Summarizing, the inhibitors identified in this study might provide a starting point toward developing novel therapies for Cantú disease. Frontiers Media S.A. 2019-05-24 /pmc/articles/PMC6543810/ /pubmed/31178728 http://dx.doi.org/10.3389/fphar.2019.00549 Text en Copyright © 2019 Chen, Garon, Wieder, Houtman, Zangerl-Plessl, Langer, van der Heyden and Stary-Weinzinger. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Chen, Xingyu
Garon, Arthur
Wieder, Marcus
Houtman, Marien J. C.
Zangerl-Plessl, Eva-Maria
Langer, Thierry
van der Heyden, Marcel A. G.
Stary-Weinzinger, Anna
Computational Identification of Novel Kir6 Channel Inhibitors
title Computational Identification of Novel Kir6 Channel Inhibitors
title_full Computational Identification of Novel Kir6 Channel Inhibitors
title_fullStr Computational Identification of Novel Kir6 Channel Inhibitors
title_full_unstemmed Computational Identification of Novel Kir6 Channel Inhibitors
title_short Computational Identification of Novel Kir6 Channel Inhibitors
title_sort computational identification of novel kir6 channel inhibitors
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543810/
https://www.ncbi.nlm.nih.gov/pubmed/31178728
http://dx.doi.org/10.3389/fphar.2019.00549
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