Details of Drug Off-Target (DOT)

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

• DOT Name: Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (NOS1AP)
• Synonyms: C-terminal PDZ ligand of neuronal nitric oxide synthase protein; Nitric oxide synthase 1 adaptor protein
• Gene Name: NOS1AP
• Related Disease:
  Arrhythmia
  Autism spectrum disorder
  Bipolar disorder
  Brain disease
  Cardiac arrest
  Cardiac failure
  Cardiovascular disease
  Congestive heart failure
  Coronary atherosclerosis
  Coronary heart disease
  Depression
  Fatty liver disease
  Glioma
  Hypertrophic cardiomyopathy
  Long QT syndrome 1
  Mental disorder
  Neoplasm
  Non-insulin dependent diabetes
  Obsessive compulsive disorder
  Post-traumatic stress disorder
  Sciatic neuropathy
  Ventricular tachycardia
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Long QT syndrome
  Neuralgia
  Brugada syndrome
  Mixed anxiety and depressive disorder
  Nephrotic syndrome, type 22
  Stroke
• UniProt ID: CAPON_HUMAN
• Pfam ID: PF00640
• Sequence:
  MPSKTKYNLVDDGHDLRIPLHNEDAFQHGICFEAKYVGSLDVPRPNSRVEIVAAMRRIRY
  EFKAKNIKKKKVSIMVSVDGVKVILKKKKKLLLLQKKEWTWDESKMLVMQDPIYRIFYVS
  HDSQDLKIFSYIARDGASNIFRCNVFKSKKKSQAMRIVRTVGQAFEVCHKLSLQHTQQNA
  DGQEDGESERNSNSSGDPGRQLTGAERASTATAEETDIDAVEVPLPGNDVLEFSRGVTDL
  DAVGKEGGSHTGSKVSHPQEPMLTASPRMLLPSSSSKPPGLGTETPLSTHHQMQLLQQLL
  QQQQQQTQVAVAQVHLLKDQLAAEAAARLEAQARVHQLLLQNKDMLQHISLLVKQVQELE
  LKLSGQNAMGSQDSLLEITFRSGALPVLCDPTTPKPEDLHSPPLGAGLADFAHPAGSPLG
  RRDCLVKLECFRFLPPEDTPPPAQGEALLGGLELIKFRESGIASEYESNTDESEERDSWS
  QEELPRLLNVLQRQELGDGLDDEIAV
• Function: Adapter protein involved in neuronal nitric-oxide (NO) synthesis regulation via its association with nNOS/NOS1. The complex formed with NOS1 and synapsins is necessary for specific NO and synapsin functions at a presynaptic level. Mediates an indirect interaction between NOS1 and RASD1 leading to enhance the ability of NOS1 to activate RASD1. Competes with DLG4 for interaction with NOS1, possibly affecting NOS1 activity by regulating the interaction between NOS1 and DLG4. In kidney podocytes, plays a role in podosomes and filopodia formation through CDC42 activation.
• Tissue Specificity: Expressed in kidney glomeruli podocytes.
• KEGG Pathway: Circadian entrainment (hsa04713)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arrhythmia	DISFF2NI	Strong	Genetic Variation	[1]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Brain disease	DIS6ZC3X	Strong	Biomarker	[4]
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[5]
Cardiac failure	DISDC067	Strong	Biomarker	[6]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[7]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[8]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[8]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[8]
Depression	DIS3XJ69	Strong	Genetic Variation	[9]
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[10]
Glioma	DIS5RPEH	Strong	Biomarker	[11]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[12]
Long QT syndrome 1	DISXK5OU	Strong	Genetic Variation	[13]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[10]
Obsessive compulsive disorder	DIS1ZMM2	Strong	Genetic Variation	[2]
Post-traumatic stress disorder	DISHL1EY	Strong	Altered Expression	[15]
Sciatic neuropathy	DISMGDKX	Strong	Biomarker	[16]
Ventricular tachycardia	DISIBXJ3	Strong	Genetic Variation	[17]
Arteriosclerosis	DISK5QGC	moderate	Genetic Variation	[7]
Atherosclerosis	DISMN9J3	moderate	Genetic Variation	[7]
Breast cancer	DIS7DPX1	moderate	Biomarker	[18]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[18]
Long QT syndrome	DISMKWS3	moderate	Genetic Variation	[13]
Neuralgia	DISWO58J	moderate	Biomarker	[19]
Brugada syndrome	DISSGN0E	Limited	Genetic Variation	[20]
Mixed anxiety and depressive disorder	DISV809X	Limited	Genetic Variation	[15]
Nephrotic syndrome, type 22	DIS0HXIU	Limited	Autosomal recessive	[21]
Stroke	DISX6UHX	Limited	Biomarker	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (NOS1AP).	[23]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (NOS1AP).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (NOS1AP).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (NOS1AP).	[31]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (NOS1AP).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (NOS1AP).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (NOS1AP).	[25]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (NOS1AP).	[26]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (NOS1AP).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (NOS1AP).	[30]

References

• [1] Polymorphisms in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome.J Am Coll Cardiol. 2010 Jun 15;55(24):2745-52. doi: 10.1016/j.jacc.2009.12.065.
• [2] Mutation screening of NOS1AP gene in a large sample of psychiatric patients and controls.BMC Med Genet. 2010 Jul 5;11:108. doi: 10.1186/1471-2350-11-108.
• [3] Increased expression in dorsolateral prefrontal cortex of CAPON in schizophrenia and bipolar disorder.PLoS Med. 2005 Oct;2(10):e263. doi: 10.1371/journal.pmed.0020263. Epub 2005 Sep 13.
• [4] Research progress in NOS1AP in neurological and psychiatric diseases.Brain Res Bull. 2016 Jul;125:99-105. doi: 10.1016/j.brainresbull.2016.05.014. Epub 2016 May 26.
• [5] Generation of two human induced pluripotent stem cell (hiPSC) lines from a long QT syndrome South African founder population.Stem Cell Res. 2019 Aug;39:101510. doi: 10.1016/j.scr.2019.101510. Epub 2019 Jul 24.
• [6] Decreased nNOS in the PVN leads to increased sympathoexcitation in chronic heart failure: role for CAPON and Ang II.Cardiovasc Res. 2011 Nov 1;92(2):348-57. doi: 10.1093/cvr/cvr217. Epub 2011 Aug 10.
• [7] Associations between NOS1AP single nucleotide polymorphisms (SNPs) and QT interval duration in four racial/ethnic groups in the Multi-Ethnic Study of Atherosclerosis (MESA).Ann Noninvasive Electrocardiol. 2013 Jan;18(1):29-40. doi: 10.1111/anec.12028.
• [8] A common NOS1AP genetic polymorphism, rs12567209 G>A, is associated with sudden cardiac death in patients with chronic heart failure in the Chinese Han population.J Card Fail. 2014 Apr;20(4):244-51. doi: 10.1016/j.cardfail.2014.01.006. Epub 2014 Jan 10.
• [9] Association of NOS1AP variants and depression phenotypes in schizophrenia.J Affect Disord. 2015 Dec 1;188:263-9. doi: 10.1016/j.jad.2015.08.069. Epub 2015 Sep 8.
• [10] Hepatic nitric oxide synthase 1 adaptor protein regulates glucose homeostasis and hepatic insulin sensitivity in obese mice depending on its PDZ binding domain.EBioMedicine. 2019 Sep;47:352-364. doi: 10.1016/j.ebiom.2019.08.033. Epub 2019 Aug 28.
• [11] Effects of Long Form of CAPON Overexpression on Glioma Cell Proliferation are Dependent on AKT/mTOR/P53 Signaling.Int J Med Sci. 2019 Apr 25;16(4):614-622. doi: 10.7150/ijms.31579. eCollection 2019.
• [12] NOS1AP Polymorphisms Modify QTc Interval Duration But Not Cardiac Arrest Risk in Hypertrophic Cardiomyopathy.J Cardiovasc Electrophysiol. 2015 Dec;26(12):1346-51. doi: 10.1111/jce.12827. Epub 2015 Oct 13.
• [13] Generation of the human induced pluripotent stem cell (hiPSC) line PSMi007-A from a Long QT Syndrome type 1 patient carrier of two common variants in the NOS1AP gene.Stem Cell Res. 2019 Apr;36:101416. doi: 10.1016/j.scr.2019.101416. Epub 2019 Mar 6.
• [14] Low Expression of CAPON in Glioma Contributes to Cell Proliferation via the Akt Signaling Pathway.Int J Mol Sci. 2016 Nov 18;17(11):1859. doi: 10.3390/ijms17111859.
• [15] Nitric oxide pathway genes (NOS1AP and NOS1) are involved in PTSD severity, depression, anxiety, stress and resilience.Gene. 2017 Aug 20;625:42-48. doi: 10.1016/j.gene.2017.04.048. Epub 2017 Apr 29.
• [16] Changes in mRNA for CAPON and Dexras1 in adult rat following sciatic nerve transection.J Chem Neuroanat. 2008 Jan;35(1):85-93. doi: 10.1016/j.jchemneu.2007.07.004. Epub 2007 Jul 31.
• [17] The genetic variation rs12143842 in NOS1AP increases idiopathic ventricular tachycardia risk in Chinese Han populations.Sci Rep. 2017 Aug 21;7(1):8356. doi: 10.1038/s41598-017-08548-z.
• [18] A protein complex of SCRIB, NOS1AP and VANGL1 regulates cell polarity and migration, and is associated with breast cancer progression.Oncogene. 2012 Aug 9;31(32):3696-708. doi: 10.1038/onc.2011.528. Epub 2011 Dec 19.
• [19] ZLc002, a putative small-molecule inhibitor of nNOS interaction with NOS1AP, suppresses inflammatory nociception and chemotherapy-induced neuropathic pain and synergizes with paclitaxel to reduce tumor cell viability.Mol Pain. 2018 Jan-Dec;14:1744806918801224. doi: 10.1177/1744806918801224. Epub 2018 Aug 29.
• [20] Association of common variants in NOS1AP gene with sudden unexplained nocturnal death syndrome in the southern Chinese Han population.Int J Legal Med. 2014 Nov;128(6):933-8. doi: 10.1007/s00414-014-0973-5. Epub 2014 Feb 7.
• [21] Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice. Sci Adv. 2021 Jan 1;7(1):eabe1386. doi: 10.1126/sciadv.abe1386. Print 2021 Jan.
• [22] Dissociating nNOS (Neuronal NO Synthase)-CAPON (Carboxy-Terminal Postsynaptic Density-95/Discs Large/Zona Occludens-1 Ligand of nNOS) Interaction Promotes Functional Recovery After Stroke via Enhanced Structural Neuroplasticity.Stroke. 2019 Mar;50(3):728-737. doi: 10.1161/STROKEAHA.118.022647.
• [23] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [24] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [25] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [26] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [27] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [28] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [29] 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.
• [30] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [31] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.