Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7I5FDX)

DOT Name	Complement component C9 (C9)
Gene Name	C9
Related Disease	Chronic renal failure ( ) Endometriosis ( ) Infertility ( ) Alzheimer disease ( ) Barrett esophagus ( ) Complement component 9 deficiency ( ) Complement deficiency ( ) Dermatomyositis ( ) Familial multiple trichoepithelioma ( ) Glomerulonephritis ( ) Hepatocellular carcinoma ( ) Malignant mesothelioma ( ) Meningococcal meningitis ( ) Myocardial infarction ( ) Neovascular age-related macular degeneration ( ) Norrie disease ( ) Opioid dependence ( ) Pancreatic cancer ( ) Polycystic kidney disease ( ) Type-1/2 diabetes ( ) X-linked reticulate pigmentary disorder ( ) Acute myelogenous leukaemia ( ) Age-related macular degeneration ( ) Bacterial infection ( ) Chronic hepatitis B virus infection ( ) Chronic kidney disease ( ) Glioblastoma multiforme ( ) Immunodeficiency ( )
UniProt ID	CO9_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	5FMW; 6DLW; 6H03; 6H04; 7NYC; 7NYD; 8B0G; 8B0H; 8DE6
Pfam ID	PF00057 ; PF01823 ; PF00090
Sequence	MSACRSFAVAICILEISILTAQYTTSYDPELTESSGSASHIDCRMSPWSEWSQCDPCLRQ MFRSRSIEVFGQFNGKRCTDAVGDRRQCVPTEPCEDAEDDCGNDFQCSTGRCIKMRLRCN GDNDCGDFSDEDDCESEPRPPCRDRVVEESELARTAGYGINILGMDPLSTPFDNEFYNGL CNRDRDGNTLTYYRRPWNVASLIYETKGEKNFRTEHYEEQIEAFKSIIQEKTSNFNAAIS LKFTPTETNKAEQCCEETASSISLHGKGSFRFSYSKNETYQLFLSYSSKKEKMFLHVKGE IHLGRFVMRNRDVVLTTTFVDDIKALPTTYEKGEYFAFLETYGTHYSSSGSLGGLYELIY VLDKASMKRKGVELKDIKRCLGYHLDVSLAFSEISVGAEFNKDDCVKRGEGRAVNITSEN LIDDVVSLIRGGTRKYAFELKEKLLRGTVIDVTDFVNWASSINDAPVLISQKLSPIYNLV PVKMKNAHLKKQNLERAIEDYINEFSVRKCHTCQNGGTVILMDGKCLCACPFKFEGIACE ISKQKISEGLPALEFPNEK
Function	Constituent of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells. C9 is the pore-forming subunit of the MAC.
Tissue Specificity	Plasma (at protein level).
KEGG Pathway	Complement and coagulation cascades (hsa04610 ) Regulation of actin cytoskeleton (hsa04810 ) Prion disease (hsa05020 ) Amoebiasis (hsa05146 ) Coro.virus disease - COVID-19 (hsa05171 ) Systemic lupus erythematosus (hsa05322 )
Reactome Pathway	Regulation of Complement cascade (R-HSA-977606 ) Terminal pathway of complement (R-HSA-166665 )

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Endometriosis	DISX1AG8	Definitive	Altered Expression	[2]
Infertility	DISAMOWP	Definitive	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[4]
Complement component 9 deficiency	DISTLE7C	Strong	Autosomal recessive	[5]
Complement deficiency	DISGN469	Strong	Genetic Variation	[6]
Dermatomyositis	DIS50C5O	Strong	Biomarker	[7]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Altered Expression	[4]
Glomerulonephritis	DISPZIQ3	Strong	Genetic Variation	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Malignant mesothelioma	DISTHJGH	Strong	Biomarker	[10]
Meningococcal meningitis	DISCKTAT	Strong	Biomarker	[11]
Myocardial infarction	DIS655KI	Strong	Biomarker	[12]
Neovascular age-related macular degeneration	DIS5S9R7	Strong	Genetic Variation	[13]
Norrie disease	DISOCDDU	Strong	Biomarker	[3]
Opioid dependence	DIS6WEHK	Strong	Biomarker	[14]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[15]
Polycystic kidney disease	DISWS3UY	Strong	Therapeutic	[16]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[17]
X-linked reticulate pigmentary disorder	DIS0RB5A	Strong	Altered Expression	[18]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[19]
Age-related macular degeneration	DIS0XS2C	moderate	Genetic Variation	[20]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[21]
Chronic hepatitis B virus infection	DISHL4NT	moderate	Genetic Variation	[22]
Chronic kidney disease	DISW82R7	Limited	Genetic Variation	[23]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[24]
Immunodeficiency	DIS093I0	Limited	Biomarker	[7]
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⏷ Show the Full List of 28 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Complement component C9 (C9).	[25]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Complement component C9 (C9).	[26]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Complement component C9 (C9).	[27]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Complement component C9 (C9).	[28]
Bosentan	DMIOGBU	Approved	Bosentan affects the expression of Complement component C9 (C9).	[30]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Complement component C9 (C9).	[33]
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⏷ Show the Full List of 6 Drug(s)

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Complement component C9 (C9).	[29]
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the phosphorylation of Complement component C9 (C9).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Complement component C9 (C9).	[32]
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References

1	A catalog of genetic loci associated with kidney function from analyses of a million individuals.Nat Genet. 2019 Jun;51(6):957-972. doi: 10.1038/s41588-019-0407-x. Epub 2019 May 31.
2	Levels of complement components iC3b, C3c, C4, and SC5b-9 in peritoneal fluid and serum of infertile women with endometriosis.Fertil Steril. 2007 Nov;88(5):1298-303. doi: 10.1016/j.fertnstert.2006.12.061. Epub 2007 May 4.
3	Deficiency of complement defense protein CD59 may contribute to neurodegeneration in Alzheimer's disease.J Neurosci. 2000 Oct 15;20(20):7505-9. doi: 10.1523/JNEUROSCI.20-20-07505.2000.
4	Evaluation of Serum Glycoprotein Biomarker Candidates for Detection of Esophageal Adenocarcinoma and Surveillance of Barrett's Esophagus.Mol Cell Proteomics. 2018 Dec;17(12):2324-2334. doi: 10.1074/mcp.RA118.000734. Epub 2018 Aug 10.
5	The human complement C9 gene: identification of two mutations causing deficiency and revision of the gene structure. J Immunol. 1997 May 15;158(10):5043-9.
6	Molecular epidemiology of C9 deficiency heterozygotes with an Arg95Stop mutation of the C9 gene in Japan.J Hum Genet. 1999;44(2):109-11. doi: 10.1007/s100380050119.
7	Hereditary complement (C9) deficiency associated with dermatomyositis.Br J Dermatol. 2001 May;144(5):1080-3. doi: 10.1046/j.1365-2133.2001.04204.x.
8	Membranoproliferative pattern of glomerular injury associated with complement component 9 deficiency due to Arg95Stop mutation.Clin Exp Nephrol. 2011 Feb;15(1):86-91. doi: 10.1007/s10157-010-0358-0. Epub 2010 Nov 6.
9	Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
10	Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool.PLoS One. 2012;7(10):e46091. doi: 10.1371/journal.pone.0046091. Epub 2012 Oct 3.
11	A non-sense mutation at Arg95 is predominant in complement 9 deficiency in Japanese.J Immunol. 1998 Feb 1;160(3):1509-13.
12	Glycoproteomic Profiling Provides Candidate Myocardial Infarction Predictors of Later Progression to Heart Failure.ACS Omega. 2019 Jan 31;4(1):1272-1280. doi: 10.1021/acsomega.8b02207. Epub 2019 Jan 15.
13	A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.Nat Genet. 2016 Feb;48(2):134-43. doi: 10.1038/ng.3448. Epub 2015 Dec 21.
14	Substance dependence low-density whole genome association study in two distinct American populations. Hum Genet. 2008 Jun;123(5):495-506. doi: 10.1007/s00439-008-0501-0. Epub 2008 Apr 26.
15	Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations.Nat Genet. 2011 Dec 11;44(1):62-6. doi: 10.1038/ng.1020.
16	Excessive activation of the alternative complement pathway in autosomal dominant polycystic kidney disease.J Intern Med. 2014 Nov;276(5):470-85. doi: 10.1111/joim.12214. Epub 2014 Mar 2.
17	Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.Nat Commun. 2019 Aug 26;10(1):3842. doi: 10.1038/s41467-019-11704-w.
18	INCREASED COMPLEMENT LEVELS IN HUMAN VITREOUS ASPIRATES OF PROLIFERATIVE DIABETIC RETINOPATHY AND RETINAL DETACHMENT EYES.Retina. 2019 Nov;39(11):2212-2218. doi: 10.1097/IAE.0000000000002288.
19	Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
20	Functional analyses of rare genetic variants in complement component C9 identified in patients with age-related macular degeneration.Hum Mol Genet. 2018 Aug 1;27(15):2678-2688. doi: 10.1093/hmg/ddy178.
21	Identification of second arginine-glycine-aspartic acid motif of ovine vitronectin as the complement C9 binding site and its implication in bacterial infection.Microbiol Immunol. 2017 Feb;61(2):75-84. doi: 10.1111/1348-0421.12468.
22	Genetic analysis of complement component 9 (C9) polymorphisms with clearance of hepatitis B virus infection.Dig Dis Sci. 2011 Sep;56(9):2735-41. doi: 10.1007/s10620-011-1657-3. Epub 2011 Mar 5.
23	Genome-wide association and functional follow-up reveals new loci for kidney function.PLoS Genet. 2012;8(3):e1002584. doi: 10.1371/journal.pgen.1002584. Epub 2012 Mar 29.
24	Identification of blood biomarkers in glioblastoma by SWATH mass spectrometry and quantitative targeted absolute proteomics.PLoS One. 2018 Mar 7;13(3):e0193799. doi: 10.1371/journal.pone.0193799. eCollection 2018.
25	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.
26	Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
27	Fetal-sex dependent genomic responses in the circulating lymphocytes of arsenic-exposed pregnant women in New Hampshire. Reprod Toxicol. 2017 Oct;73:184-195. doi: 10.1016/j.reprotox.2017.07.023. Epub 2017 Aug 6.
28	Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
29	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.
30	Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
31	Effects of olanzapine on serum protein phosphorylation patterns in patients with schizophrenia. Proteomics Clin Appl. 2015 Oct;9(9-10):907-16. doi: 10.1002/prca.201400148. Epub 2015 May 15.
32	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.
33	Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.