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Chen X, Garon A, Wieder M, et al. Computational Identification of Novel Kir6 Channel Inhibitors. Front Pharmacol. 2019;10:549doi: 10.3389/fphar.2019.00549.
Chen, X., Garon, A., Wieder, M., Houtman, M. J. C., Zangerl-Plessl, E. M., Langer, T., van der Heyden, M. A. G., & Stary-Weinzinger, A. (2019). Computational Identification of Novel Kir6 Channel Inhibitors. Frontiers in pharmacology, 10549. https://doi.org/10.3389/fphar.2019.00549
Chen, Xingyu, et al. "Computational Identification of Novel Kir6 Channel Inhibitors." Frontiers in pharmacology vol. 10 (2019): 549. doi: https://doi.org/10.3389/fphar.2019.00549
Chen X, Garon A, Wieder M, Houtman MJC, Zangerl-Plessl EM, Langer T, van der Heyden MAG, Stary-Weinzinger A. Computational Identification of Novel Kir6 Channel Inhibitors. Front Pharmacol. 2019 May 24;10:549. doi: 10.3389/fphar.2019.00549. eCollection 2019. PMID: 31178728; PMCID: PMC6543810.
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Front Pharmacol. 2019 May 24;10:549. doi: 10.3389/fphar.2019.00549. eCollection 2019.

Computational Identification of Novel Kir6 Channel Inhibitors.

Frontiers in pharmacology

Xingyu Chen, Arthur Garon, Marcus Wieder, Marien J C Houtman, Eva-Maria Zangerl-Plessl, Thierry Langer, Marcel A G van der Heyden, Anna Stary-Weinzinger

Affiliations

  1. Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria.
  2. Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.
  3. Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands.

PMID: 31178728 PMCID: PMC6543810 DOI: 10.3389/fphar.2019.00549

Abstract

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

Keywords: Cantú syndrome; KATP channel; channelopathy; dynamic pharmacophore; electrophysiology; molecular dynamics simulation

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