Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGYZWR6)

• DOT Name: Sodium channel protein type 5 subunit alpha (SCN5A)
• Synonyms: Sodium channel protein cardiac muscle subunit alpha; Sodium channel protein type V subunit alpha; Voltage-gated sodium channel subunit alpha Nav1.5; hH1
• Gene Name: SCN5A
• Related Disease:
  Brugada syndrome
  Brugada syndrome 1
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1E
  Familial long QT syndrome
  Long QT syndrome 3
  Progressive familial heart block, type 1A
  Sick sinus syndrome 1
  Atrial standstill
  Familial atrial fibrillation
  Familial sick sinus syndrome
  Obsolete familial isolated dilated cardiomyopathy
  Paroxysmal familial ventricular fibrillation
  Progressive familial heart block
  Catecholaminergic polymorphic ventricular tachycardia
  Short QT syndrome
  Arrhythmogenic right ventricular cardiomyopathy
• UniProt ID: SCN5A_HUMAN
• PDB ID: 2KBI; 2L53; 4DCK; 4DJC; 4JQ0; 4OVN; 5DBR; 6LQA; 6MUD; 7DTC; 7L83
• Pfam ID: PF00520 ; PF06512 ; PF11933
• Sequence:
  MANFLLPRGTSSFRRFTRESLAAIEKRMAEKQARGSTTLQESREGLPEEEAPRPQLDLQA
  SKKLPDLYGNPPQELIGEPLEDLDPFYSTQKTFIVLNKGKTIFRFSATNALYVLSPFHPI
  RRAAVKILVHSLFNMLIMCTILTNCVFMAQHDPPPWTKYVEYTFTAIYTFESLVKILARG
  FCLHAFTFLRDPWNWLDFSVIIMAYTTEFVDLGNVSALRTFRVLRALKTISVISGLKTIV
  GALIQSVKKLADVMVLTVFCLSVFALIGLQLFMGNLRHKCVRNFTALNGTNGSVEADGLV
  WESLDLYLSDPENYLLKNGTSDVLLCGNSSDAGTCPEGYRCLKAGENPDHGYTSFDSFAW
  AFLALFRLMTQDCWERLYQQTLRSAGKIYMIFFMLVIFLGSFYLVNLILAVVAMAYEEQN
  QATIAETEEKEKRFQEAMEMLKKEHEALTIRGVDTVSRSSLEMSPLAPVNSHERRSKRRK
  RMSSGTEECGEDRLPKSDSEDGPRAMNHLSLTRGLSRTSMKPRSSRGSIFTFRRRDLGSE
  ADFADDENSTAGESESHHTSLLVPWPLRRTSAQGQPSPGTSAPGHALHGKKNSTVDCNGV
  VSLLGAGDPEATSPGSHLLRPVMLEHPPDTTTPSEEPGGPQMLTSQAPCVDGFEEPGARQ
  RALSAVSVLTSALEELEESRHKCPPCWNRLAQRYLIWECCPLWMSIKQGVKLVVMDPFTD
  LTITMCIVLNTLFMALEHYNMTSEFEEMLQVGNLVFTGIFTAEMTFKIIALDPYYYFQQG
  WNIFDSIIVILSLMELGLSRMSNLSVLRSFRLLRVFKLAKSWPTLNTLIKIIGNSVGALG
  NLTLVLAIIVFIFAVVGMQLFGKNYSELRDSDSGLLPRWHMMDFFHAFLIIFRILCGEWI
  ETMWDCMEVSGQSLCLLVFLLVMVIGNLVVLNLFLALLLSSFSADNLTAPDEDREMNNLQ
  LALARIQRGLRFVKRTTWDFCCGLLRQRPQKPAALAAQGQLPSCIATPYSPPPPETEKVP
  PTRKETRFEEGEQPGQGTPGDPEPVCVPIAVAESDTDDQEEDEENSLGTEEESSKQQESQ
  PVSGGPEAPPDSRTWSQVSATASSEAEASASQADWRQQWKAEPQAPGCGETPEDSCSEGS
  TADMTNTAELLEQIPDLGQDVKDPEDCFTEGCVRRCPCCAVDTTQAPGKVWWRLRKTCYH
  IVEHSWFETFIIFMILLSSGALAFEDIYLEERKTIKVLLEYADKMFTYVFVLEMLLKWVA
  YGFKKYFTNAWCWLDFLIVDVSLVSLVANTLGFAEMGPIKSLRTLRALRPLRALSRFEGM
  RVVVNALVGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKFGRCINQTEGDLPLNYTIVNN
  KSQCESLNLTGELYWTKVKVNFDNVGAGYLALLQVATFKGWMDIMYAAVDSRGYEEQPQW
  EYNLYMYIYFVIFIIFGSFFTLNLFIGVIIDNFNQQKKKLGGQDIFMTEEQKKYYNAMKK
  LGSKKPQKPIPRPLNKYQGFIFDIVTKQAFDVTIMFLICLNMVTMMVETDDQSPEKINIL
  AKINLLFVAIFTGECIVKLAALRHYYFTNSWNIFDFVVVILSIVGTVLSDIIQKYFFSPT
  LFRVIRLARIGRILRLIRGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYSIFGMANFA
  YVKWEAGIDDMFNFQTFANSMLCLFQITTSAGWDGLLSPILNTGPPYCDPTLPNSNGSRG
  DCGSPAVGILFFTTYIIISFLIVVNMYIAIILENFSVATEESTEPLSEDDFDMFYEIWEK
  FDPEATQFIEYSVLSDFADALSEPLRIAKPNQISLINMDLPMVSGDRIHCMDILFAFTKR
  VLGESGEMDALKIQMEEKFMAANPSKISYEPITTTLRRKHEEVSAMVIQRAFRRHLLQRS
  LKHASFLFRQQAGSGLSEEDAPEREGLIAYVMSENFSRPLGPPSSSSISSTSFPPSYDSV
  TRATSDNLQVRGSDYSHSEDLADFPPSPDRDRESIV
• Function: This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels.
• Tissue Specificity: Found in jejunal circular smooth muscle cells (at protein level). Expressed in human atrial and ventricular cardiac muscle but not in adult skeletal muscle, brain, myometrium, liver, or spleen. Isoform 4 is expressed in brain.
• KEGG Pathway: Adrenergic sig.ling in cardiomyocytes (hsa04261)
• Reactome Pathway:
  Phase 0 - rapid depolarisation (R-HSA-5576892)
  Interaction between L1 and Ankyrins (R-HSA-445095)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brugada syndrome	DISSGN0E	Definitive	Autosomal dominant	[1]
Brugada syndrome 1	DISKBA7V	Definitive	Autosomal dominant	[2]
Dilated cardiomyopathy	DISX608J	Definitive	Autosomal dominant	[1]
Dilated cardiomyopathy 1E	DISE2ZR1	Definitive	Autosomal dominant	[3]
Familial long QT syndrome	DISRNNCY	Definitive	Autosomal dominant	[1]
Long QT syndrome 3	DISQG4EA	Definitive	Autosomal dominant	[3]
Progressive familial heart block, type 1A	DISUPY6A	Strong	Autosomal dominant	[2]
Sick sinus syndrome 1	DISVOM8L	Strong	Autosomal recessive	[4]
Atrial standstill	DISFHGZA	Supportive	Autosomal dominant	[5]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[6]
Familial sick sinus syndrome	DISFVIMO	Supportive	Autosomal dominant	[7]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[8]
Paroxysmal familial ventricular fibrillation	DISRM7IX	Supportive	Autosomal dominant	[9]
Progressive familial heart block	DISNEF3B	Supportive	Autosomal dominant	[10]
Catecholaminergic polymorphic ventricular tachycardia	DISSAS1A	Disputed	Autosomal dominant	[1]
Short QT syndrome	DISOI9X1	Disputed	Autosomal dominant	[1]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 17 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Propranolol	DM79NTF	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Propranolol.	[27]
Atenolol	DMNKG1Z	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Atenolol.	[27]
Flecainide	DMSQDLE	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) affects the response to substance of Flecainide.	[28]
Quinidine	DMLPICK	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Quinidine.	[27]
Lidocaine	DML4ZOT	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) affects the response to substance of Lidocaine.	[29]
Hydrochlorothiazide	DMUSZHD	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Hydrochlorothiazide.	[27]
Procainamide	DMNMXR8	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Procainamide.	[27]
Disopyramide	DM5SYZP	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Disopyramide.	[27]
Diltiazem	DMAI7ZV	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Diltiazem.	[27]
Sotalol	DML60TN	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Sotalol.	[27]
Propafenone	DMPIBJK	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Propafenone.	[27]
Dofetilide	DMPN1TW	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Dofetilide.	[27]
Tocainide	DMYNMDP	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Tocainide.	[27]
Ajmaline	DMDJW5K	Approved	Sodium channel protein type 5 subunit alpha (SCN5A) affects the response to substance of Ajmaline.	[30]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Sodium channel protein type 5 subunit alpha (SCN5A) affects the response to substance of Amiodarone.	[31]
Verapamil	DMA7PEW	Phase 2/3 Trial	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Verapamil.	[27]
Terfenadine	DM4KLPT	Withdrawn from market	Sodium channel protein type 5 subunit alpha (SCN5A) increases the Sudden cardiac death ADR of Terfenadine.	[27]

20 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Sodium channel protein type 5 subunit alpha (SCN5A).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium channel protein type 5 subunit alpha (SCN5A).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sodium channel protein type 5 subunit alpha (SCN5A).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[14]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[15]
Piroxicam	DMTK234	Approved	Piroxicam decreases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[15]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Sodium channel protein type 5 subunit alpha (SCN5A).	[12]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Sodium channel protein type 5 subunit alpha (SCN5A).	[12]
Nefazodone	DM4ZS8M	Approved	Nefazodone affects the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[16]
Crizotinib	DM4F29C	Approved	Crizotinib decreases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[17]
Luvox	DMJKROX	Approved	Luvox decreases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[18]
Meloxicam	DM2AR7L	Approved	Meloxicam decreases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[15]
Retigabine	DMGNYIH	Approved	Retigabine affects the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[19]
Telmisartan	DMS3GX2	Phase 3 Trial	Telmisartan increases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[23]
Nimesulide	DMR1NMD	Terminated	Nimesulide decreases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[15]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[24]
9-phenanthrol	DMJFBQ1	Investigative	9-phenanthrol decreases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[25]
Ibogaine	DM3HJX7	Investigative	Ibogaine decreases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[26]
18-Methoxycoronaridine	DMTJ384	Investigative	18-Methoxycoronaridine decreases the activity of Sodium channel protein type 5 subunit alpha (SCN5A).	[26]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisapride	DMY7PED	Approved	Cisapride increases the localization of Sodium channel protein type 5 subunit alpha (SCN5A).	[20]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Sodium channel protein type 5 subunit alpha (SCN5A).	[22]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Homozygous SCN5A mutation in Brugada syndrome with monomorphic ventricular tachycardia and structural heart abnormalities. Europace. 2007 Jun;9(6):391-7. doi: 10.1093/europace/eum053. Epub 2007 Apr 18.
• [5] A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill. Circ Res. 2003 Jan 10;92(1):14-22. doi: 10.1161/01.res.0000050585.07097.d7.
• [6] A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation. J Am Coll Cardiol. 2008 Oct 14;52(16):1326-34. doi: 10.1016/j.jacc.2008.07.013.
• [7] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [8] SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation. 2004 Oct 12;110(15):2163-7. doi: 10.1161/01.CIR.0000144458.58660.BB. Epub 2004 Oct 4.
• [9] A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome. FEBS Lett. 2000 Aug 11;479(1-2):29-34. doi: 10.1016/s0014-5793(00)01875-5.
• [10] Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lengre disease. J Am Coll Cardiol. 2003 Feb 19;41(4):643-52. doi: 10.1016/s0735-1097(02)02864-4.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [13] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [14] Inhibitory effects of cannabidiol on voltage-dependent sodium currents. J Biol Chem. 2018 Oct 26;293(43):16546-16558. doi: 10.1074/jbc.RA118.004929. Epub 2018 Sep 14.
• [15] Regulatory effects of non-steroidal anti-inflammatory drugs on cardiac ion channels Nav1.5 and Kv11.1. Chem Biol Interact. 2021 Apr 1;338:109425. doi: 10.1016/j.cbi.2021.109425. Epub 2021 Feb 19.
• [16] Evaluation of nefazodone-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2016 Apr 1;296:42-53. doi: 10.1016/j.taap.2016.01.015. Epub 2016 Jan 25.
• [17] Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes. Toxicol Appl Pharmacol. 2013 Oct 1;272(1):245-55.
• [18] Brugada syndrome ECG provoked by the selective serotonin reuptake inhibitor fluvoxamine. Europace. 2010 Feb;12(2):282-3. doi: 10.1093/europace/eup332. Epub 2009 Oct 29.
• [19] Modulation of the heart's electrical properties by the anticonvulsant drug retigabine. Toxicol Appl Pharmacol. 2017 Aug 15;329:309-317. doi: 10.1016/j.taap.2017.06.018. Epub 2017 Jun 20.
• [20] New mechanism contributing to drug-induced arrhythmia: rescue of a misprocessed LQT3 mutant. Circulation. 2005 Nov 22;112(21):3239-46. doi: 10.1161/CIRCULATIONAHA.105.564008.
• [21] Differential regulation of tefluthrin and telmisartan on the gating charges of I(Na) activation and inactivation as well as on resurgent and persistent I(Na) in a pituitary cell line (GH(3)). Toxicol Lett. 2018 Mar 15;285:104-112. doi: 10.1016/j.toxlet.2018.01.002. Epub 2018 Jan 3.
• [22] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [23] Use of human stem cell derived cardiomyocytes to examine sunitinib mediated cardiotoxicity and electrophysiological alterations. Toxicol Appl Pharmacol. 2011 Nov 15;257(1):74-83. doi: 10.1016/j.taap.2011.08.020. Epub 2011 Aug 27.
• [24] Unmasking of brugada syndrome by lithium. Circulation. 2005 Sep 13;112(11):1527-31. doi: 10.1161/CIRCULATIONAHA.105.548487. Epub 2005 Sep 6.
• [25] The transient receptor potential melastatin 4 channel inhibitor 9-phenanthrol modulates cardiac sodium channel. Br J Pharmacol. 2018 Dec;175(23):4325-4337. doi: 10.1111/bph.14490. Epub 2018 Oct 14.
• [26] Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: a study to assess the drug's cardiac ion channel profile. Toxicol Appl Pharmacol. 2013 Dec 1;273(2):259-68. doi: 10.1016/j.taap.2013.05.012. Epub 2013 May 22.
• [27] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [28] Flecainide test in Brugada syndrome: a reproducible but risky tool. Pacing Clin Electrophysiol. 2003 Jan;26(1P2):338-41. doi: 10.1046/j.1460-9592.2003.00045.x.
• [29] Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel. Circ Res. 2008 Aug 15;103(4):396-404. doi: 10.1161/CIRCRESAHA.108.172619. Epub 2008 Jul 3.
• [30] Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation. 2000 Feb 8;101(5):510-5. doi: 10.1161/01.cir.101.5.510.
• [31] Ethnic-Related Sodium Voltage-Gated Channel Subunit 5 Polymorphisms Shape the In Vitro Pharmacological Action of Amiodarone upon Na(v)1.5. Mol Pharmacol. 2021 Jun;99(6):448-459. doi: 10.1124/molpharm.120.000176. Epub 2021 Apr 6.