Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDMZ3LT)

• DOT Name: Coagulation factor V (F5)
• Synonyms: Activated protein C cofactor; Proaccelerin, labile factor
• Gene Name: F5
• Related Disease:
  Congenital factor V deficiency
  Thrombophilia due to activated protein C resistance
  East Texas bleeding disorder
• UniProt ID: FA5_HUMAN
• PDB ID: 1CZS; 1CZT; 1CZV; 3P6Z; 3P70; 3S9C; 7KVE; 7KVF; 7KXY; 7TPP; 7TPQ; 8FDG; 8TN9
• Pfam ID: PF07732 ; PF00754
• Sequence:
  MFPGCPRLWVLVVLGTSWVGWGSQGTEAAQLRQFYVAAQGISWSYRPEPTNSSLNLSVTS
  FKKIVYREYEPYFKKEKPQSTISGLLGPTLYAEVGDIIKVHFKNKADKPLSIHPQGIRYS
  KLSEGASYLDHTFPAEKMDDAVAPGREYTYEWSISEDSGPTHDDPPCLTHIYYSHENLIE
  DFNSGLIGPLLICKKGTLTEGGTQKTFDKQIVLLFAVFDESKSWSQSSSLMYTVNGYVNG
  TMPDITVCAHDHISWHLLGMSSGPELFSIHFNGQVLEQNHHKVSAITLVSATSTTANMTV
  GPEGKWIISSLTPKHLQAGMQAYIDIKNCPKKTRNLKKITREQRRHMKRWEYFIAAEEVI
  WDYAPVIPANMDKKYRSQHLDNFSNQIGKHYKKVMYTQYEDESFTKHTVNPNMKEDGILG
  PIIRAQVRDTLKIVFKNMASRPYSIYPHGVTFSPYEDEVNSSFTSGRNNTMIRAVQPGET
  YTYKWNILEFDEPTENDAQCLTRPYYSDVDIMRDIASGLIGLLLICKSRSLDRRGIQRAA
  DIEQQAVFAVFDENKSWYLEDNINKFCENPDEVKRDDPKFYESNIMSTINGYVPESITTL
  GFCFDDTVQWHFCSVGTQNEILTIHFTGHSFIYGKRHEDTLTLFPMRGESVTVTMDNVGT
  WMLTSMNSSPRSKKLRLKFRDVKCIPDDDEDSYEIFEPPESTVMATRKMHDRLEPEDEES
  DADYDYQNRLAAALGIRSFRNSSLNQEEEEFNLTALALENGTEFVSSNTDIIVGSNYSSP
  SNISKFTVNNLAEPQKAPSHQQATTAGSPLRHLIGKNSVLNSSTAEHSSPYSEDPIEDPL
  QPDVTGIRLLSLGAGEFKSQEHAKHKGPKVERDQAAKHRFSWMKLLAHKVGRHLSQDTGS
  PSGMRPWEDLPSQDTGSPSRMRPWKDPPSDLLLLKQSNSSKILVGRWHLASEKGSYEIIQ
  DTDEDTAVNNWLISPQNASRAWGESTPLANKPGKQSGHPKFPRVRHKSLQVRQDGGKSRL
  KKSQFLIKTRKKKKEKHTHHAPLSPRTFHPLRSEAYNTFSERRLKHSLVLHKSNETSLPT
  DLNQTLPSMDFGWIASLPDHNQNSSNDTGQASCPPGLYQTVPPEEHYQTFPIQDPDQMHS
  TSDPSHRSSSPELSEMLEYDRSHKSFPTDISQMSPSSEHEVWQTVISPDLSQVTLSPELS
  QTNLSPDLSHTTLSPELIQRNLSPALGQMPISPDLSHTTLSPDLSHTTLSLDLSQTNLSP
  ELSQTNLSPALGQMPLSPDLSHTTLSLDFSQTNLSPELSHMTLSPELSQTNLSPALGQMP
  ISPDLSHTTLSLDFSQTNLSPELSQTNLSPALGQMPLSPDPSHTTLSLDLSQTNLSPELS
  QTNLSPDLSEMPLFADLSQIPLTPDLDQMTLSPDLGETDLSPNFGQMSLSPDLSQVTLSP
  DISDTTLLPDLSQISPPPDLDQIFYPSESSQSLLLQEFNESFPYPDLGQMPSPSSPTLND
  TFLSKEFNPLVIVGLSKDGTDYIEIIPKEEVQSSEDDYAEIDYVPYDDPYKTDVRTNINS
  SRDPDNIAAWYLRSNNGNRRNYYIAAEEISWDYSEFVQRETDIEDSDDIPEDTTYKKVVF
  RKYLDSTFTKRDPRGEYEEHLGILGPIIRAEVDDVIQVRFKNLASRPYSLHAHGLSYEKS
  SEGKTYEDDSPEWFKEDNAVQPNSSYTYVWHATERSGPESPGSACRAWAYYSAVNPEKDI
  HSGLIGPLLICQKGILHKDSNMPMDMREFVLLFMTFDEKKSWYYEKKSRSSWRLTSSEMK
  KSHEFHAINGMIYSLPGLKMYEQEWVRLHLLNIGGSQDIHVVHFHGQTLLENGNKQHQLG
  VWPLLPGSFKTLEMKASKPGWWLLNTEVGENQRAGMQTPFLIMDRDCRMPMGLSTGIISD
  SQIKASEFLGYWEPRLARLNNGGSYNAWSVEKLAAEFASKPWIQVDMQKEVIITGIQTQG
  AKHYLKSCYTTEFYVAYSSNQINWQIFKGNSTRNVMYFNGNSDASTIKENQFDPPIVARY
  IRISPTRAYNRPTLRLELQGCEVNGCSTPLGMENGKIENKQITASSFKKSWWGDYWEPFR
  ARLNAQGRVNAWQAKANNNKQWLEIDLLKIKKITAIITQGCKSLSSEMYVKSYTIHYSEQ
  GVEWKPYRLKSSMVDKIFEGNTNTKGHVKNFFNPPIISRFIRVIPKTWNQSIALRLELFG
  CDIY
• Function: Central regulator of hemostasis. It serves as a critical cofactor for the prothrombinase activity of factor Xa that results in the activation of prothrombin to thrombin.
• Tissue Specificity: Plasma.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Common Pathway of Fibrin Clot Formation (R-HSA-140875)
  COPII-mediated vesicle transport (R-HSA-204005)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Cargo concentration in the ER (R-HSA-5694530)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Platelet degranulation (R-HSA-114608)
• BioCyc Pathway: MetaCyc:G66-30677-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital factor V deficiency	DISSFUFN	Definitive	Autosomal recessive	[1]
Thrombophilia due to activated protein C resistance	DIST6SYL	Definitive	Autosomal dominant	[1]
East Texas bleeding disorder	DISF1XPJ	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Coagulation factor V (F5) decreases the response to substance of Tretinoin.	[20]
Chlorothiazide	DMLHESP	Approved	Coagulation factor V (F5) increases the Thromboembolic event ADR of Chlorothiazide.	[21]
Warfarin	DMJYCVW	Approved	Coagulation factor V (F5) affects the response to substance of Warfarin.	[22]
Tamoxifen	DMLB0EZ	Approved	Coagulation factor V (F5) increases the Thromboembolic event ADR of Tamoxifen.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Coagulation factor V (F5).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Coagulation factor V (F5).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Coagulation factor V (F5).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Coagulation factor V (F5).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Coagulation factor V (F5).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Coagulation factor V (F5).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Coagulation factor V (F5).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Coagulation factor V (F5).	[9]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Coagulation factor V (F5).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Coagulation factor V (F5).	[11]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin decreases the activity of Coagulation factor V (F5).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Coagulation factor V (F5).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Coagulation factor V (F5).	[15]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Coagulation factor V (F5).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Coagulation factor V (F5).	[17]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Coagulation factor V (F5).	[18]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Coagulation factor V (F5).	[19]

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 Coagulation factor V (F5).	[13]

References

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• [2] Coagulation factor V(A2440G) causes east Texas bleeding disorder via TFPI. J Clin Invest. 2013 Sep;123(9):3777-87. doi: 10.1172/JCI69091. Epub 2013 Aug 27.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Atorvastatin and quinapril inhibit blood coagulation in patients with coronary artery disease following 28 days of therapy. J Thromb Haemost. 2006 Nov;4(11):2397-404. doi: 10.1111/j.1538-7836.2006.02165.x. Epub 2006 Aug 14.
• [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] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [17] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [18] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [19] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [20] Thrombosis during all-trans-retinoic acid therapy in a child with acute promyelocytic leukemia and factor VQ 506 mutation. Pediatr Hematol Oncol. 2000 Mar;17(2):177-80. doi: 10.1080/088800100276541.
• [21] Factor V Leiden mutation and thromboembolism risk in women receiving adjuvant tamoxifen for breast cancer. J Natl Cancer Inst. 2010 Jul 7;102(13):942-9. doi: 10.1093/jnci/djq211. Epub 2010 Jun 16.
• [22] Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study. Pharmacogenet Genomics. 2009 Oct;19(10):800-12. doi: 10.1097/FPC.0b013e3283317ab5.