Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSL3OIC)

• DOT Name: Complement C5 (C5)
• Synonyms: C3 and PZP-like alpha-2-macroglobulin domain-containing protein 4
• Gene Name: C5
• Related Disease: Complement component 5 deficiency
• UniProt ID: CO5_HUMAN
• PDB ID: 1CFA ; 1KJS ; 1XWE ; 3CU7 ; 3HQA ; 3HQB ; 3KLS ; 3KM9 ; 3PRX ; 3PVM ; 4A5W ; 4E0S ; 4P39 ; 4UU9 ; 5B4P ; 5B71 ; 5HCC ; 5HCD ; 5HCE ; 5I5K ; 6H03 ; 6H04 ; 6RPT ; 6RQJ ; 7AD6 ; 7AD7 ; 7NYC ; 7NYD ; 7Y64 ; 8B0F ; 8B0G ; 8B0H ; 8HK5 ; 8HQC ; 8IA2 ; 8JZZ
• Pfam ID: PF00207 ; PF07703 ; PF07677 ; PF01821 ; PF21309 ; PF17790 ; PF01835 ; PF17791 ; PF17789 ; PF01759 ; PF07678
• Sequence:
  MGLLGILCFLIFLGKTWGQEQTYVISAPKIFRVGASENIVIQVYGYTEAFDATISIKSYP
  DKKFSYSSGHVHLSSENKFQNSAILTIQPKQLPGGQNPVSYVYLEVVSKHFSKSKRMPIT
  YDNGFLFIHTDKPVYTPDQSVKVRVYSLNDDLKPAKRETVLTFIDPEGSEVDMVEEIDHI
  GIISFPDFKIPSNPRYGMWTIKAKYKEDFSTTGTAYFEVKEYVLPHFSVSIEPEYNFIGY
  KNFKNFEITIKARYFYNKVVTEADVYITFGIREDLKDDQKEMMQTAMQNTMLINGIAQVT
  FDSETAVKELSYYSLEDLNNKYLYIAVTVIESTGGFSEEAEIPGIKYVLSPYKLNLVATP
  LFLKPGIPYPIKVQVKDSLDQLVGGVPVTLNAQTIDVNQETSDLDPSKSVTRVDDGVASF
  VLNLPSGVTVLEFNVKTDAPDLPEENQAREGYRAIAYSSLSQSYLYIDWTDNHKALLVGE
  HLNIIVTPKSPYIDKITHYNYLILSKGKIIHFGTREKFSDASYQSINIPVTQNMVPSSRL
  LVYYIVTGEQTAELVSDSVWLNIEEKCGNQLQVHLSPDADAYSPGQTVSLNMATGMDSWV
  ALAAVDSAVYGVQRGAKKPLERVFQFLEKSDLGCGAGGGLNNANVFHLAGLTFLTNANAD
  DSQENDEPCKEILRPRRTLQKKIEEIAAKYKHSVVKKCCYDGACVNNDETCEQRAARISL
  GPRCIKAFTECCVVASQLRANISHKDMQLGRLHMKTLLPVSKPEIRSYFPESWLWEVHLV
  PRRKQLQFALPDSLTTWEIQGVGISNTGICVADTVKAKVFKDVFLEMNIPYSVVRGEQIQ
  LKGTVYNYRTSGMQFCVKMSAVEGICTSESPVIDHQGTKSSKCVRQKVEGSSSHLVTFTV
  LPLEIGLHNINFSLETWFGKEILVKTLRVVPEGVKRESYSGVTLDPRGIYGTISRRKEFP
  YRIPLDLVPKTEIKRILSVKGLLVGEILSAVLSQEGINILTHLPKGSAEAELMSVVPVFY
  VFHYLETGNHWNIFHSDPLIEKQKLKKKLKEGMLSIMSYRNADYSYSVWKGGSASTWLTA
  FALRVLGQVNKYVEQNQNSICNSLLWLVENYQLDNGSFKENSQYQPIKLQGTLPVEAREN
  SLYLTAFTVIGIRKAFDICPLVKIDTALIKADNFLLENTLPAQSTFTLAISAYALSLGDK
  THPQFRSIVSALKREALVKGNPPIYRFWKDNLQHKDSSVPNTGTARMVETTAYALLTSLN
  LKDINYVNPVIKWLSEEQRYGGGFYSTQDTINAIEGLTEYSLLVKQLRLSMDIDVSYKHK
  GALHNYKMTDKNFLGRPVEVLLNDDLIVSTGFGSGLATVHVTTVVHKTSTSEEVCSFYLK
  IDTQDIEASHYRGYGNSDYKRIVACASYKPSREESSSGSSHAVMDISLPTGISANEEDLK
  ALVEGVDQLFTDYQIKDGHVILQLNSIPSSDFLCVRFRIFELFEVGFLSPATFTVYEYHR
  PDKQCTMFYSTSNIKIQKVCEGAACKCVEADCGQMQEELDLTISAETRKQTACKPEIAYA
  YKVSITSITVENVFVKYKATLLDIYKTGEAVAEKDSEITFIKKVTCTNAELVKGRQYLIM
  GKEALQIKYNFSFRYIYPLDSLTWIEYWPRDTTCSSCQAFLANLDEFAEDIFLNGC
• Function: Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C6 complex is the foundation upon which the lytic complex is assembled.; [C5a anaphylatoxin]: Derived from proteolytic degradation of complement C5, C5a anaphylatoxin is a mediator of local inflammatory process. Binding to the receptor C5AR1 induces a variety of responses including intracellular calcium release, contraction of smooth muscle, increased vascular permeability, and histamine release from mast cells and basophilic leukocytes. C5a is also a potent chemokine which stimulates the locomotion of polymorphonuclear leukocytes and directs their migration toward sites of inflammation.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Complement and coagulation cascades (hsa04610)
  Neutrophil extracellular trap formation (hsa04613)
  Regulation of actin cytoskeleton (hsa04810)
  Alcoholic liver disease (hsa04936)
  Prion disease (hsa05020)
  Pertussis (hsa05133)
  Staphylococcus aureus infection (hsa05150)
  Herpes simplex virus 1 infection (hsa05168)
  Coro.virus disease - COVID-19 (hsa05171)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Activation of C3 and C5 (R-HSA-174577)
  Peptide ligand-binding receptors (R-HSA-375276)
  G alpha (i) signalling events (R-HSA-418594)
  Regulation of Complement cascade (R-HSA-977606)
  Terminal pathway of complement (R-HSA-166665)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complement component 5 deficiency	DISLWX2Y	Strong	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
LTB4	DME26RS	Phase 2	Complement C5 (C5) increases the abundance of LTB4.	[23]

18 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 C5 (C5).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Complement C5 (C5).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Complement C5 (C5).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Complement C5 (C5).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Complement C5 (C5).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Complement C5 (C5).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Complement C5 (C5).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Complement C5 (C5).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Complement C5 (C5).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Complement C5 (C5).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Complement C5 (C5).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Complement C5 (C5).	[7]
Ardeparin	DMYRX8B	Approved	Ardeparin decreases the expression of Complement C5 (C5).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Complement C5 (C5).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Complement C5 (C5).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Complement C5 (C5).	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Complement C5 (C5).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Complement C5 (C5).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the phosphorylation of Complement C5 (C5).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Complement C5 (C5).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chondroitin sulfate	DM0N19Y	Phase 4	Chondroitin sulfate increases the cleavage of Complement C5 (C5).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the response to substance of Complement C5 (C5).	[17]

References

• [1] Molecular characterization of three new mutations causing C5 deficiency in two non-related families. Mol Immunol. 2009 Jul;46(11-12):2340-7. doi: 10.1016/j.molimm.2009.03.026. Epub 2009 May 2.
• [2] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [3] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] 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.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [12] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [13] Effect of thrombosis on complement activation and neutrophil degranulation during in vitro hemodialysis. J Am Soc Nephrol. 1994 Jul;5(1):110-5. doi: 10.1681/ASN.V51110.
• [14] 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.
• [15] Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med. 2008 Jun 5;358(23):2457-67. doi: 10.1056/NEJMoa0803200. Epub 2008 Apr 23.
• [16] 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.
• [17] Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst Biol. 2009 Mar 10;3:31. doi: 10.1186/1752-0509-3-31.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] 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.
• [20] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [21] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [23] Role of 5-lipoxygenase products in the local accumulation of neutrophils in dermal inflammation in the rabbit. J Immunol. 1999 Sep 15;163(6):3449-58.