Discovery of a novel Nav1.5 inhibitor reducing cardiac conduction via structure-based virtual screening and assays

  • Acta Pharmacol Sin. 2026 Jan 1. doi: 10.1038/s41401-025-01679-4.
Ying-Ying Wang  #  1  2 ,  Gao-Ang Wang  #  1 ,  Qing You  3 ,  Yi-Fei Liu  1 ,  Wang-Lin Qu  1 ,  Yi-Hong Chen  1 ,  Chen-Zhang Mu  1 ,  Xi Zhou  4  5 ,  Min Liu  2 ,  Wei Yang  6 ,  Ting-Jun Hou  7
Affiliations
  • 1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 2. Department of Biophysics and Neurology, Center for Membrane Receptors and Brain Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
  • 3. Department of Pharmacology, School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
  • 4. The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
  • 5. Peptide and small molecule drug R&D platform, Furong Laboratory, Hunan Normal University, Changsha, 410081, China.
  • 6. Department of Biophysics and Neurology, Center for Membrane Receptors and Brain Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China. [email protected].
  • 7. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. [email protected].
  • # Contributed equally.
PMID: 41478879 DOI: 10.1038/s41401-025-01679-4
Abstract

Nav1.5 is the main Sodium Channel subtype in the heart, playing a crucial role in maintaining regular cardiac electrical activity. It is a well-established therapeutic target for class I antiarrhythmic drugs used to treat both inherited and acquired arrhythmias. In this study, we report a highly effective (IC50 = 1.38 ± 0.28 μM) and novel Nav1.5 inhibitor, KH2, identified through an integrated drug discovery approach. Molecular dynamics (MD) simulations and experimental findings reveal that, unlike traditional class I antiarrhythmic drugs, KH2 shows a completely novel binding mechanism. Moreover, using electrophysiological mapping systems on rat isolated hearts, we found that KH2 significantly reduced cardiac conduction, highlighting its potential as a therapeutic agent for arrhythmias. Our finding of KH2 provided a valuable reference for designing drugs targeting Nav1.5 to treat arrhythmias.

Keywords
MD simulation; Nav1.5 inhibitors; antiarrhythmic drugs; structure-based virtual screening.
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