Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7UIGTP)

• DOT Name: Complexin-1 (CPLX1)
• Synonyms: Complexin I; CPX I; Synaphin-2
• Gene Name: CPLX1
• Related Disease:
  Parkinson disease
  Alzheimer disease
  Anxiety
  Anxiety disorder
  Behcet disease
  Bipolar depression
  Bipolar disorder
  Cerebellar ataxia
  Depression
  Developmental and epileptic encephalopathy, 63
  Dravet syndrome
  Epilepsy
  Non-insulin dependent diabetes
  Psychotic disorder
  Schizoaffective disorder
  Intellectual disability
  Familial infantile myoclonic epilepsy
• UniProt ID: CPLX1_HUMAN
• PDB ID: 3RK3; 3RL0
• Pfam ID: PF05835
• Sequence:
  MEFVMKQALGGATKDMGKMLGGDEEKDPDAAKKEEERQEALRQAEEERKAKYAKMEAERE
  AVRQGIRDKYGIKKKEEREAEAQAAMEANSEGSLTRPKKAIPPGCGDEVEEEDESILDTV
  IKYLPGPLQDMLKK
• Function: Positively regulates a late step in exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles. Organizes the SNAREs into a cross-linked zigzag topology that, when interposed between the vesicle and plasma membranes, is incompatible with fusion, thereby preventing SNAREs from releasing neurotransmitters until an action potential arrives at the synapse. Also involved in glucose-induced secretion of insulin by pancreatic beta-cells. Essential for motor behavior.
• Tissue Specificity: Nervous system. In hippocampus and cerebellum, expressed mainly by inhibitory neurons. Overexpressed in substantia nigra from patients with Parkinson disease.
• KEGG Pathway: Sy.ptic vesicle cycle (hsa04721)
• Reactome Pathway:
  Norepinephrine Neurotransmitter Release Cycle (R-HSA-181430)
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)
  Dopamine Neurotransmitter Release Cycle (R-HSA-212676)
  Acetylcholine Neurotransmitter Release Cycle (R-HSA-264642)
  GABA synthesis, release, reuptake and degradation (R-HSA-888590)
  Serotonin Neurotransmitter Release Cycle (R-HSA-181429)

Molecular Interaction Atlas (MIA) of This DOT

17 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	Altered Expression	[2]
Anxiety	DISIJDBA	Strong	Biomarker	[3]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[3]
Behcet disease	DISSYMBS	Strong	Biomarker	[4]
Bipolar depression	DISA75FU	Strong	Biomarker	[5]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[6]
Depression	DIS3XJ69	Strong	Biomarker	[3]
Developmental and epileptic encephalopathy, 63	DISTNCZ8	Strong	Autosomal recessive	[7]
Dravet syndrome	DISJF7LY	Strong	Genetic Variation	[6]
Epilepsy	DISBB28L	Strong	Genetic Variation	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[8]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[5]
Schizoaffective disorder	DISLBW6B	Strong	Biomarker	[5]
Intellectual disability	DISMBNXP	moderate	Biomarker	[6]
Familial infantile myoclonic epilepsy	DISELJ0F	Supportive	Autosomal recessive	[6]

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 Complexin-1 (CPLX1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Complexin-1 (CPLX1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Complexin-1 (CPLX1).	[16]

5 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 Complexin-1 (CPLX1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Complexin-1 (CPLX1).	[11]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Complexin-1 (CPLX1).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Complexin-1 (CPLX1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Complexin-1 (CPLX1).	[15]

References

• [1] Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease.Dis Model Mech. 2017 May 1;10(5):619-631. doi: 10.1242/dmm.028035. Epub 2017 Jan 20.
• [2] The Proteome of the Dentate Terminal Zone of the Perforant Path Indicates Presynaptic Impairment in Alzheimer Disease.Mol Cell Proteomics. 2020 Jan;19(1):128-141. doi: 10.1074/mcp.RA119.001737. Epub 2019 Nov 7.
• [3] Melatonin ameliorates anxiety and depression-like behaviors and modulates proteomic changes in triple transgenic mice of Alzheimer's disease.Biofactors. 2017 Jul 8;43(4):593-611. doi: 10.1002/biof.1369. Epub 2017 Jun 13.
• [4] Increased complexin-1 and decreased miR-185 expression levels in Behet's disease with and without neurological involvement.Neurol Sci. 2016 Mar;37(3):411-6. doi: 10.1007/s10072-015-2419-3. Epub 2015 Nov 14.
• [5] Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium.Mol Psychiatry. 2004 Jun;9(6):609-20, 544. doi: 10.1038/sj.mp.4001471.
• [6] Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID. Eur J Hum Genet. 2017 Jun;25(7):889-893. doi: 10.1038/ejhg.2017.52. Epub 2017 Apr 19.
• [7] Complexins regulate a late step in Ca2+-dependent neurotransmitter release. Cell. 2001 Jan 12;104(1):71-81. doi: 10.1016/s0092-8674(01)00192-1.
• [8] Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding.Diabetologia. 2016 Apr;59(4):799-812. doi: 10.1007/s00125-015-3852-9. Epub 2016 Jan 11.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [13] 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.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] 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.
• [16] 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.