Weiwei Xie, Jiaming Gao, Yingran Liang, Chenxing Huang, Boyong Zhang, Xiaonan Chen, Xi Yao, Guo Nan, Honghua Wu, Yuefei Wang, Lin Wu, Taiyi Wang, Yan Zhu
{"title":"Identification of Lauric Acid as a Potent Sodium Channel Na<sub>V</sub>1.5 Blocker from Compound Chinese Medicine Wenxin Keli.","authors":"Weiwei Xie, Jiaming Gao, Yingran Liang, Chenxing Huang, Boyong Zhang, Xiaonan Chen, Xi Yao, Guo Nan, Honghua Wu, Yuefei Wang, Lin Wu, Taiyi Wang, Yan Zhu","doi":"10.2147/DDDT.S485723","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>The major cardiac voltage-gated sodium channel Na<sub>V</sub>1.5 (I<sub>Na</sub>) is essential for cardiac action potential initiation and subsequent propagation. Compound Chinese medicine Wenxin Keli (WXKL) has been shown to suppress arrhythmias and heart failure. However, its active components have not been fully elucidated. This study focused on identifying the active inhibitor of I<sub>Na</sub> in WXKL and exploring their mode of action in electrophysiological conduction.</p><p><strong>Methods: </strong>A chemical fraction library was constructed from an aqueous extract of WXKL and screened using an automated patch-clamping system in cells stably expressing the Na<sub>V</sub>1.5 gene SCN5A. Candidate fractions with I<sub>Na</sub>-inhibition activity were analyzed by HPLC-ESI-IT-TOF-MS and GC-MS to identify the ingredients. Na<sub>V</sub>1.5 blocker molecules identified by single-cell electrocardiogram were tested in hiPSC-derived cardiomyocytes. We evaluated the SCN5A inhibitory potential of Wenxin Keli effective monomer employing molecular docking and molecular dynamics simulation approaches.</p><p><strong>Results: </strong>A primary screen of the WXKL chemical library identified five fractions that significantly inhibited the Na<sub>V</sub>1.5 channel, with one of them rich in poly-saturated fatty acids. Molecular structural characterization revealed the presence of lauric acid, myristic acid, palmitic acid, and stearic acid in the active subfraction. Electrophysiological characterization demonstrated lauric acid (LA) as the most effective monomer for I<sub>Na</sub>-inhibition with an IC<sub>50</sub> at 27.40 ± 12.78 μM. LA shifted the steady-state inactivation of I<sub>Na</sub> to more negative potentials and decreased the amplitude of extracellular field potential in hiPSC-derived cardiomyocytes. We demonstrate for the first time that naturally poly-saturated fatty acid, lauric acid, as a potential novel I<sub>Na</sub> blocker. Molecular docking and molecular dynamics simulation suggested that LA binds to the Na<sub>V</sub>1.5 protein, with a significant binding affinity forming interactions with functionally essential residues and blocks the inward flow of Na<sup>+</sup>. Mechanistically, lauric acid acts on the fast inactivation of Na<sub>V</sub>1.5 alter electrophysiology conduction of hiPSC-derived cardiomyocytes and contribute to the antiarrhythmic effect of WXKL.</p><p><strong>Conclusion: </strong>Lauric acid is a potent blocker for sodium channel Na<sub>V</sub>1.5 and alleviates arrhythmia via inhibiting I<sub>Na</sub>.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"141-157"},"PeriodicalIF":4.7000,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727701/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Design, Development and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/DDDT.S485723","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: The major cardiac voltage-gated sodium channel NaV1.5 (INa) is essential for cardiac action potential initiation and subsequent propagation. Compound Chinese medicine Wenxin Keli (WXKL) has been shown to suppress arrhythmias and heart failure. However, its active components have not been fully elucidated. This study focused on identifying the active inhibitor of INa in WXKL and exploring their mode of action in electrophysiological conduction.
Methods: A chemical fraction library was constructed from an aqueous extract of WXKL and screened using an automated patch-clamping system in cells stably expressing the NaV1.5 gene SCN5A. Candidate fractions with INa-inhibition activity were analyzed by HPLC-ESI-IT-TOF-MS and GC-MS to identify the ingredients. NaV1.5 blocker molecules identified by single-cell electrocardiogram were tested in hiPSC-derived cardiomyocytes. We evaluated the SCN5A inhibitory potential of Wenxin Keli effective monomer employing molecular docking and molecular dynamics simulation approaches.
Results: A primary screen of the WXKL chemical library identified five fractions that significantly inhibited the NaV1.5 channel, with one of them rich in poly-saturated fatty acids. Molecular structural characterization revealed the presence of lauric acid, myristic acid, palmitic acid, and stearic acid in the active subfraction. Electrophysiological characterization demonstrated lauric acid (LA) as the most effective monomer for INa-inhibition with an IC50 at 27.40 ± 12.78 μM. LA shifted the steady-state inactivation of INa to more negative potentials and decreased the amplitude of extracellular field potential in hiPSC-derived cardiomyocytes. We demonstrate for the first time that naturally poly-saturated fatty acid, lauric acid, as a potential novel INa blocker. Molecular docking and molecular dynamics simulation suggested that LA binds to the NaV1.5 protein, with a significant binding affinity forming interactions with functionally essential residues and blocks the inward flow of Na+. Mechanistically, lauric acid acts on the fast inactivation of NaV1.5 alter electrophysiology conduction of hiPSC-derived cardiomyocytes and contribute to the antiarrhythmic effect of WXKL.
Conclusion: Lauric acid is a potent blocker for sodium channel NaV1.5 and alleviates arrhythmia via inhibiting INa.
期刊介绍：
Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications.
The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas.
Specific topics covered by the journal include:
Drug target identification and validation
Phenotypic screening and target deconvolution
Biochemical analyses of drug targets and their pathways
New methods or relevant applications in molecular/drug design and computer-aided drug discovery*
Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes)
Structural or molecular biological studies elucidating molecular recognition processes
Fragment-based drug discovery
Pharmaceutical/red biotechnology
Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products**
Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development
Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing)
Preclinical development studies
Translational animal models
Mechanisms of action and signalling pathways
Toxicology
Gene therapy, cell therapy and immunotherapy
Personalized medicine and pharmacogenomics
Clinical drug evaluation
Patient safety and sustained use of medicines.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
