摘要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.