Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLNRXB6)

• DOT Name: Complement factor D (CFD)
• Synonyms: EC 3.4.21.46; Adipsin; C3 convertase activator; Properdin factor D
• Gene Name: CFD
• Related Disease: Recurrent Neisseria infections due to factor D deficiency
• UniProt ID: CFAD_HUMAN
• PDB ID: 1BIO ; 1DFP ; 1DIC ; 1DST ; 1DSU ; 1FDP ; 1HFD ; 2XW9 ; 2XWA ; 2XWB ; 4CBN ; 4CBO ; 4D9R ; 5FBE ; 5FBI ; 5FCK ; 5MT0 ; 5MT4 ; 5NAR ; 5NAT ; 5NAW ; 5NB6 ; 5NB7 ; 5NBA ; 5TCA ; 5TCC ; 6FTY ; 6FTZ ; 6FUG ; 6FUH ; 6FUI ; 6FUJ ; 6FUT ; 6QMR ; 6QMT ; 6VMJ ; 6VMK ; 8D95 ; 8DEA ; 8DG6
• EC Number: 3.4.21.46
• Pfam ID: PF00089
• Sequence:
  MHSWERLAVLVLLGAAACAAPPRGRILGGREAEAHARPYMASVQLNGAHLCGGVLVAEQW
  VLSAAHCLEDAADGKVQVLLGAHSLSQPEPSKRLYDVLRAVPHPDSQPDTIDHDLLLLQL
  SEKATLGPAVRPLPWQRVDRDVAPGTLCDVAGWGIVNHAGRRPDSLQHVLLPVLDRATCN
  RRTHHDGAITERLMCAESNRRDSCKGDSGGPLVCGGVLEGVVTSGSRVCGNRKKPGIYTR
  VASYAAWIDSVLA
• Function: Factor D cleaves factor B when the latter is complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. Its function is homologous to that of C1s in the classical pathway.
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  Staphylococcus aureus infection (hsa05150)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Alternative complement activation (R-HSA-173736)
  Neutrophil degranulation (R-HSA-6798695)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Recurrent Neisseria infections due to factor D deficiency	DISD57HO	Strong	Autosomal recessive	[1]

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 factor D (CFD).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Complement factor D (CFD).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Complement factor D (CFD).	[17]

15 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 Complement factor D (CFD).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Complement factor D (CFD).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Complement factor D (CFD).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Complement factor D (CFD).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Complement factor D (CFD).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Complement factor D (CFD).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Complement factor D (CFD).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Complement factor D (CFD).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Complement factor D (CFD).	[10]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Complement factor D (CFD).	[11]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Complement factor D (CFD).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Complement factor D (CFD).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Complement factor D (CFD).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Complement factor D (CFD).	[18]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Complement factor D (CFD).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the secretion of Complement factor D (CFD).	[14]

References

• [1] A family with complement factor D deficiency. J Clin Invest. 2001 Jul;108(2):233-40. doi: 10.1172/JCI12023.
• [2] 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.
• [3] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] 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.
• [7] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [8] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] Dexamethasone and the inflammatory response in explants of human omental adipose tissue. Mol Cell Endocrinol. 2010 Feb 5;315(1-2):292-8.
• [10] Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3951-6. doi: 10.1073/pnas.96.7.3951.
• [11] Deletion of circadian gene Per1 alleviates acute ethanol-induced hepatotoxicity in mice. Toxicology. 2013 Dec 15;314(2-3):193-201. doi: 10.1016/j.tox.2013.09.009. Epub 2013 Oct 18.
• [12] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [17] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [18] Bisphenol A induces differentiation of human preadipocytes in the absence of glucocorticoid and is inhibited by an estrogen-receptor antagonist. Nutr Diabetes. 2014 Jan 13;4(1):e102. doi: 10.1038/nutd.2013.43.
• [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.