Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA0ZNIU)

• DOT Name: Complement C1r subcomponent (C1R)
• Synonyms: EC 3.4.21.41; Complement component 1 subcomponent r
• Gene Name: C1R
• Related Disease:
  Parkinson disease
  Alzheimer disease
  Colorectal carcinoma
  Complement deficiency
  Ehlers-Danlos syndrome
  Ehlers-Danlos syndrome, periodontal type 1
  Lupus
  Renal fibrosis
  Systemic lupus erythematosus
  Osteoarthritis
  Autosomal systemic lupus erythematosus type 16
  Ehlers-Danlos syndrome, periodontitis type
  Endometriosis
• UniProt ID: C1R_HUMAN
• PDB ID: 1APQ; 1GPZ; 1MD7; 1MD8; 2QY0; 6F1C; 6F1D; 6F1H; 6F39
• EC Number: 3.4.21.41
• Pfam ID: PF00431 ; PF14670 ; PF00084 ; PF00089
• Sequence:
  MWLLYLLVPALFCRAGGSIPIPQKLFGEVTSPLFPKPYPNNFETTTVITVPTGYRVKLVF
  QQFDLEPSEGCFYDYVKISADKKSLGRFCGQLGSPLGNPPGKKEFMSQGNKMLLTFHTDF
  SNEENGTIMFYKGFLAYYQAVDLDECASRSKSGEEDPQPQCQHLCHNYVGGYFCSCRPGY
  ELQEDTHSCQAECSSELYTEASGYISSLEYPRSYPPDLRCNYSIRVERGLTLHLKFLEPF
  DIDDHQQVHCPYDQLQIYANGKNIGEFCGKQRPPDLDTSSNAVDLLFFTDESGDSRGWKL
  RYTTEIIKCPQPKTLDEFTIIQNLQPQYQFRDYFIATCKQGYQLIEGNQVLHSFTAVCQD
  DGTWHRAMPRCKIKDCGQPRNLPNGDFRYTTTMGVNTYKARIQYYCHEPYYKMQTRAGSR
  ESEQGVYTCTAQGIWKNEQKGEKIPRCLPVCGKPVNPVEQRQRIIGGQKAKMGNFPWQVF
  TNIHGRGGGALLGDRWILTAAHTLYPKEHEAQSNASLDVFLGHTNVEELMKLGNHPIRRV
  SVHPDYRQDESYNFEGDIALLELENSVTLGPNLLPICLPDNDTFYDLGLMGYVSGFGVME
  EKIAHDLRFVRLPVANPQACENWLRGKNRMDVFSQNMFCAGHPSLKQDACQGDSGGVFAV
  RDPNTDRWVATGIVSWGIGCSRGYGFYTKVLNYVDWIKKEMEEED
• Function: C1r B chain is a serine protease that combines with C1q and C1s to form C1, the first component of the classical pathway of the complement system.
• KEGG Pathway:
  Phagosome (hsa04145)
  Complement and coagulation cascades (hsa04610)
  Pertussis (hsa05133)
  Staphylococcus aureus infection (hsa05150)
  Coro.virus disease - COVID-19 (hsa05171)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Classical antibody-mediated complement activation (R-HSA-173623)
  Regulation of Complement cascade (R-HSA-977606)
  Initial triggering of complement (R-HSA-166663)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Complement deficiency	DISGN469	Strong	Biomarker	[4]
Ehlers-Danlos syndrome	DISSVBRR	Strong	Genetic Variation	[5]
Ehlers-Danlos syndrome, periodontal type 1	DIS4VQMI	Strong	Autosomal dominant	[6]
Lupus	DISOKJWA	Strong	Genetic Variation	[7]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[8]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[4]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[9]
Autosomal systemic lupus erythematosus type 16	DIS9RKY9	Supportive	Autosomal dominant	[4]
Ehlers-Danlos syndrome, periodontitis type	DISB3QMD	Supportive	Autosomal dominant	[10]
Endometriosis	DISX1AG8	Limited	Biomarker	[11]

3 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 Complement C1r subcomponent (C1R).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Complement C1r subcomponent (C1R).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Complement C1r subcomponent (C1R).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Complement C1r subcomponent (C1R).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Complement C1r subcomponent (C1R).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Complement C1r subcomponent (C1R).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Complement C1r subcomponent (C1R).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Complement C1r subcomponent (C1R).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Complement C1r subcomponent (C1R).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Complement C1r subcomponent (C1R).	[19]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Complement C1r subcomponent (C1R).	[20]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Complement C1r subcomponent (C1R).	[21]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Complement C1r subcomponent (C1R).	[22]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Complement C1r subcomponent (C1R).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Complement C1r subcomponent (C1R).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Complement C1r subcomponent (C1R).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Complement C1r subcomponent (C1R).	[28]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	D-glucose decreases the secretion of Complement C1r subcomponent (C1R).	[29]

References

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• [4] Brief Report: Deficiency of Complement 1r Subcomponent in Early-Onset Systemic Lupus Erythematosus: The Role of Disease-Modifying Alleles in a Monogenic Disease. Arthritis Rheumatol. 2017 Sep;69(9):1832-1839. doi: 10.1002/art.40158. Epub 2017 Jul 10.
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• [10] Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement. Am J Hum Genet. 2016 Nov 3;99(5):1005-1014. doi: 10.1016/j.ajhg.2016.08.019. Epub 2016 Oct 13.
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• [17] 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.
• [18] 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.
• [19] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [20] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [21] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [22] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [23] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [24] 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.
• [25] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [26] 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.
• [27] 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.
• [28] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [29] Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects. Biochim Biophys Acta. 2014 Sep;1844(9):1511-22. doi: 10.1016/j.bbapap.2014.04.023. Epub 2014 May 5.