Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8VHLKY)

• DOT Name: Thrombomodulin (THBD)
• Synonyms: TM; Fetomodulin; CD antigen CD141
• Gene Name: THBD
• Related Disease:
  Atypical hemolytic-uremic syndrome with thrombomodulin anomaly
  Thrombomodulin-related bleeding disorder
• UniProt ID: TRBM_HUMAN
• PDB ID: 1ADX; 1DQB; 1DX5; 1EGT; 1FGD; 1FGE; 1HLT; 1TMR; 1ZAQ; 2ADX; 3GIS; 5TO3; 7T4R
• Pfam ID: PF12662 ; PF07645 ; PF14670 ; PF00059 ; PF09064
• Sequence:
  MLGVLVLGALALAGLGFPAPAEPQPGGSQCVEHDCFALYPGPATFLNASQICDGLRGHLM
  TVRSSVAADVISLLLNGDGGVGRRRLWIGLQLPPGCGDPKRLGPLRGFQWVTGDNNTSYS
  RWARLDLNGAPLCGPLCVAVSAAEATVPSEPIWEEQQCEVKADGFLCEFHFPATCRPLAV
  EPGAAAAAVSITYGTPFAARGADFQALPVGSSAAVAPLGLQLMCTAPPGAVQGHWAREAP
  GAWDCSVENGGCEHACNAIPGAPRCQCPAGAALQADGRSCTASATQSCNDLCEHFCVPNP
  DQPGSYSCMCETGYRLAADQHRCEDVDDCILEPSPCPQRCVNTQGGFECHCYPNYDLVDG
  ECVEPVDPCFRANCEYQCQPLNQTSYLCVCAEGFAPIPHEPHRCQMFCNQTACPADCDPN
  TQASCECPEGYILDDGFICTDIDECENGGFCSGVCHNLPGTFECICGPDSALARHIGTDC
  DSGKVDGGDSGSGEPPPSPTPGSTLTPPAVGLVHSGLLIGISIASLCLVVALLALLCHLR
  KKQGAARAKMEYKCAAPSKEVVLQHVRTERTPQRL
• Function: Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated.
• Tissue Specificity: Endothelial cells are unique in synthesizing thrombomodulin.
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Cell surface interactions at the vascular wall (R-HSA-202733)
  Common Pathway of Fibrin Clot Formation (R-HSA-140875)
• BioCyc Pathway: MetaCyc:ENSG00000178726-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atypical hemolytic-uremic syndrome with thrombomodulin anomaly	DIS8TF4K	Strong	Autosomal dominant	[1]
Thrombomodulin-related bleeding disorder	DISLLGU6	Strong	Autosomal dominant	[2]

This DOT Affected the Drug Response of 8 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Thrombomodulin (THBD) increases the Thrombosis ADR of Ciclosporin.	[30]
Temozolomide	DMKECZD	Approved	Thrombomodulin (THBD) affects the response to substance of Temozolomide.	[31]
Selenium	DM25CGV	Approved	Thrombomodulin (THBD) increases the Blood and lymphatic system disorders ADR of Selenium.	[30]
Paclitaxel	DMLB81S	Approved	Thrombomodulin (THBD) decreases the response to substance of Paclitaxel.	[32]
DTI-015	DMXZRW0	Approved	Thrombomodulin (THBD) affects the response to substance of DTI-015.	[31]
Thalidomide	DM70BU5	Approved	Thrombomodulin (THBD) increases the Deep vein thrombosis ADR of Thalidomide.	[30]
Beta-carotene	DM0RXBT	Approved	Thrombomodulin (THBD) increases the Blood and lymphatic system disorders ADR of Beta-carotene.	[30]
Pentoxifylline	DMU3DNC	Approved	Thrombomodulin (THBD) increases the Blood and lymphatic system disorders ADR of Pentoxifylline.	[30]

2 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 Thrombomodulin (THBD).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Thrombomodulin (THBD).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Thrombomodulin (THBD).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Thrombomodulin (THBD).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Thrombomodulin (THBD).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Thrombomodulin (THBD).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Thrombomodulin (THBD).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Thrombomodulin (THBD).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Thrombomodulin (THBD).	[10]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Thrombomodulin (THBD).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Thrombomodulin (THBD).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Thrombomodulin (THBD).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Thrombomodulin (THBD).	[14]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Thrombomodulin (THBD).	[15]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Thrombomodulin (THBD).	[16]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Thrombomodulin (THBD).	[17]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Thrombomodulin (THBD).	[18]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Thrombomodulin (THBD).	[19]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Thrombomodulin (THBD).	[20]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Thrombomodulin (THBD).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Thrombomodulin (THBD).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Thrombomodulin (THBD).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Thrombomodulin (THBD).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Thrombomodulin (THBD).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Thrombomodulin (THBD).	[27]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Thrombomodulin (THBD).	[28]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Thrombomodulin (THBD).	[29]

References

• [1] Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009 Jul 23;361(4):345-57. doi: 10.1056/NEJMoa0810739.
• [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] 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] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [5] Hyaluronic acid and endothelial damage due to paracetamol-induced hepatotoxicity. Liver Int. 2003 Apr;23(2):110-5. doi: 10.1034/j.1600-0676.2003.00808.x.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [9] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [10] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [14] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [15] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [16] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [17] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [18] Increased levels of activated factor VII and decreased plasma protein S activity and circulating thrombomodulin during use of oral contraceptives. Thromb Haemost. 1996 Nov;76(5):729-34.
• [19] Cytoskeletal activation and altered gene expression in endothelial barrier regulation by simvastatin. Am J Respir Cell Mol Biol. 2004 May;30(5):662-70. doi: 10.1165/rcmb.2003-0267OC. Epub 2003 Nov 20.
• [20] Activation of SIRT1 by resveratrol induces KLF2 expression conferring an endothelial vasoprotective phenotype. Cardiovasc Res. 2010 Feb 1;85(3):514-9. doi: 10.1093/cvr/cvp337. Epub 2009 Oct 8.
• [21] Promyelocytic leukemia retinoid signaling targets regulate apoptosis,tissue factor and thrombomodulin expression. Haematologica. 2004 Mar;89(3):286-95.
• [22] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [23] 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.
• [24] Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014 May;13(5):1142-54.
• [25] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [26] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] Non-nutritional sweeteners effects on endothelial vascular function. Toxicol In Vitro. 2020 Feb;62:104694. doi: 10.1016/j.tiv.2019.104694. Epub 2019 Oct 23.
• [29] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.
• [30] 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.
• [31] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [32] Involvement of high mobility group box 1 in the development and maintenance of chemotherapy-induced peripheral neuropathy in rats. Toxicology. 2016 Jul 15;365:48-58. doi: 10.1016/j.tox.2016.07.016. Epub 2016 Jul 27.