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

Ying-ying Wang; Gao-ang Wang; Qing You; Yi-fei Liu; Wang-lin Qu; Yi-hong Chen; Chen-zhang Mu; Xi Zhou; Min Liu; Wei Yang; Ting-jun Hou

doi:10.1038/s41401-025-01679-4

Discovery of a novel Na_v1.5 inhibitor reducing cardiac conduction via structure-based virtual screening and assays

Ying-ying Wang^1,2, Gao-ang Wang¹, Qing You³, Yi-fei Liu¹, Wang-lin Qu¹, Yi-hong Chen¹, Chen-zhang Mu¹, Xi Zhou^4,5, Min Liu², Wei Yang², Ting-jun Hou¹
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
Correspondence to: Wei Yang: yangwei@zju.edu.cn, Ting-jun Hou: tingjunhou@zju.edu.cn,
DOI: 10.1038/s41401-025-01679-4

Received: 28 May 2025

Accepted: 21 September 2025

Advance online: 1 January 2026

Abstract

Na_v1.5 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 Na_v1.5 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 Na_v1.5 to treat arrhythmias.

Keywords: Na_v1.5 inhibitors; antiarrhythmic drugs; structure-based virtual screening; MD simulation

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Discovery of a novel Na_v1.5 inhibitor reducing cardiac conduction via structure-based virtual screening and assays

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