Discovery of Small-Molecule Inhibitors of the KCNQ1/Kv7.1 Potassium Channel with Virtual Screening and Functional Validation in Electrophysiological Assays and KCNQ1-Knockout Neural Stem Cells

  • ACS Chem Neurosci. 2026 Jun 3;17(11):2203-2218. doi: 10.1021/acschemneuro.6c00197.
Kazi Asraful Alam  1 ,  Josep Martí-Solans  2 ,  Dorothea Schall  3 ,  Sumit Kumar  1  4 ,  Shahid Muhammad Iqbal  2 ,  Knut Teigen  1 ,  Simone Berkel  3 ,  Daniela Mauceri  5  6 ,  Bengt Erik Haug  4 ,  Sara I Liin  7 ,  Timothy Lynagh  2 ,  Aurora Martinez  1  8 ,  Jan Haavik  1  9
Affiliations
  • 1. Department of Biomedicine, University of Bergen, Bergen 5007, Norway.
  • 2. Michael Sars Centre, University of Bergen, Bergen 5006, Norway.
  • 3. Institute of Human Genetics, Heidelberg University, Heidelberg 69120, Germany.
  • 4. Department of Chemistry, University of Bergen, Bergen 5007, Norway.
  • 5. Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), Heidelberg University, Heidelberg 69120, Germany.
  • 6. Institute of Anatomy and Cell Biology, Dept. Molecular and Cellular Neuroscience, University of Marburg, Marburg 35037, Germany.
  • 7. Department of Biomedical and Clinical Sciences, Linköping University, Linköping 58185, Sweden.
  • 8. Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen 5009, Norway.
  • 9. Division of Psychiatry, Haukeland University Hospital, Bergen 5009, Norway.
PMID: 42165438 DOI: 10.1021/acschemneuro.6c00197
Abstract

Voltage-gated Potassium Channel KCNQ1 (Kv7.1) plays a critical role in electrical excitability in the heart, gut, and brain. Together with the auxiliary subunit KCNE1, KCNQ1 generates a slow delayed rectifier current (IKs) that is essential for cardiac repolarization. Mutations and dysregulation of this channel are found in channelopathies leading to sudden death, long-QT syndrome, atrial fibrillation, epilepsy, deafness, diabetes, and neuropsychiatric disorders. Although KCNQ1 and related potassium channels are promising therapeutic targets, there are few potent, selective, and therapeutically safe inhibitors and activators available for these proteins. A virtual screening of 36,374 compounds was conducted against KCNQ1, followed by in silico analyses that identified eight potential ligand candidates for experimental evaluation using human KCNQ1 coexpressed with KCNE1 in Xenopus laevis oocytes. Electrophysiological recordings showed that the benzodiazepine-based ligand Zinc13732787 was a potent inhibitor of the channel complex, without affecting KCNQ2/KCNQ3. Based on virtual screening and molecular docking, the 1-(3-chlorophenyl)-urea substituent on the benzodiazepine core is important for selective inhibition of KCNQ1/KCNE1, as further supported by structure-activity relationship and stereochemical exploration of Zinc13732787. Furthermore, low concentrations of Zinc13732787 reduced neurite outgrowth in human neuronal stem cells (NSCs), mirroring the phenotype observed in homozygous KCNQ1-knockout cells. Importantly, Zinc13732787 did not affect NSC proliferation, nor did it induce cytotoxicity. In homozygous KCNQ1-knockout NSCs, compound Zinc13732787 had no effect on neurite outgrowth, indicating high target specificity. These findings suggest that this compound is a valuable tool for investigating the physiological and pathological roles of KCNQ1 across various tissues. Additionally, it could be used as a precursor for novel antiarrhythmic agents as well as for epilepsy and neuropsychiatric conditions.

Keywords
KCNQ1/KCNE1; arrhythmia; benzodiazepines; drug discovery; ion channels; neurite growth; virtual screening.
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