Details of Drug Off-Target (DOT)

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

• DOT Name: von Willebrand factor A domain-containing protein 1
• Gene Name: VWA1
• Related Disease:
  Neuronopathy, distal hereditary motor, autosomal recessive 7
  Neuronopathy, distal hereditary motor, autosomal recessive 5
• UniProt ID: VWA1_HUMAN
• Pfam ID: PF00041 ; PF00092
• Sequence:
  MLPWTALGLALSLRLALARSGAERGPPASAPRGDLMFLLDSSASVSHYEFSRVREFVGQL
  VAPLPLGTGALRASLVHVGSRPYTEFPFGQHSSGEAAQDAVRASAQRMGDTHTGLALVYA
  KEQLFAEASGARPGVPKVLVWVTDGGSSDPVGPPMQELKDLGVTVFIVSTGRGNFLELSA
  AASAPAEKHLHFVDVDDLHIIVQELRGSILDAMRPQQLHATEITSSGFRLAWPPLLTADS
  GYYVLELVPSAQPGAARRQQLPGNATDWIWAGLDPDTDYDVALVPESNVRLLRPQILRVR
  TRPGEAGPGASGPESGAGPAPTQLAALPAPEEAGPERIVISHARPRSLRVSWAPALGSAA
  ALGYHVQFGPLRGGEAQRVEVPAGRNCTTLQGLAPGTAYLVTVTAAFRSGRESALSAKAC
  TPDGPRPRPRPVPRAPTPGTASREP
• Function: Promotes matrix assembly. Involved in the organization of skeletal muscles and in the formation of neuromuscular junctions (Probable).
• Reactome Pathway:
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuronopathy, distal hereditary motor, autosomal recessive 7	DIS9SK2V	Strong	Autosomal recessive	[1]
Neuronopathy, distal hereditary motor, autosomal recessive 5	DIS3E3YO	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of von Willebrand factor A domain-containing protein 1.	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of von Willebrand factor A domain-containing protein 1.	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of von Willebrand factor A domain-containing protein 1.	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of von Willebrand factor A domain-containing protein 1.	[15]

9 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 von Willebrand factor A domain-containing protein 1.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of von Willebrand factor A domain-containing protein 1.	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of von Willebrand factor A domain-containing protein 1.	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of von Willebrand factor A domain-containing protein 1.	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of von Willebrand factor A domain-containing protein 1.	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of von Willebrand factor A domain-containing protein 1.	[10]
Aspirin	DM672AH	Approved	Aspirin increases the expression of von Willebrand factor A domain-containing protein 1.	[11]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of von Willebrand factor A domain-containing protein 1.	[12]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of von Willebrand factor A domain-containing protein 1.	[14]

References

• [1] Bi-allelic truncating mutations in VWA1 cause neuromyopathy. Brain. 2021 Mar 3;144(2):574-583. doi: 10.1093/brain/awaa418.
• [2] An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy. Brain. 2021 Mar 3;144(2):584-600. doi: 10.1093/brain/awaa420.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Effects of aspirin on metastasis-associated gene expression detected by cDNA microarray. Acta Pharmacol Sin. 2004 Oct;25(10):1327-33.
• [12] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [13] 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.
• [14] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.