Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ3BD8U)

• DOT Name: Disks large homolog 2 (DLG2)
• Synonyms: Channel-associated protein of synapse-110; Chapsyn-110; Postsynaptic density protein PSD-93
• Gene Name: DLG2
• Related Disease:
  Alzheimer disease
  Amyloidosis
  Attention deficit hyperactivity disorder
  Bipolar disorder
  Breast neoplasm
  Cardiovascular disease
  Epithelial ovarian cancer
  Kidney neoplasm
  Major depressive disorder
  Neoplasm
  Neurodevelopmental disorder
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Rheumatoid arthritis
  Wilms tumor
  Intellectual disability
  Chronic obstructive pulmonary disease
  Melanoma
  Myopia
  Parkinson disease
• UniProt ID: DLG2_HUMAN
• PDB ID: 2BYG; 2HE2
• Pfam ID: PF00625 ; PF10608 ; PF00595 ; PF10600 ; PF00018
• Sequence:
  MFFACYCALRTNVKKYRYQDEDAPHDHSLPRLTHEVRGPELVHVSEKNLSQIENVHGYVL
  QSHISPLKASPAPIIVNTDTLDTIPYVNGTEIEYEFEEITLERGNSGLGFSIAGGTDNPH
  IGDDPGIFITKIIPGGAAAEDGRLRVNDCILRVNEVDVSEVSHSKAVEALKEAGSIVRLY
  VRRRRPILETVVEIKLFKGPKGLGFSIAGGVGNQHIPGDNSIYVTKIIDGGAAQKDGRLQ
  VGDRLLMVNNYSLEEVTHEEAVAILKNTSEVVYLKVGKPTTIYMTDPYGPPDITHSYSPP
  MENHLLSGNNGTLEYKTSLPPISPGRYSPIPKHMLVDDDYTRPPEPVYSTVNKLCDKPAS
  PRHYSPVECDKSFLLSAPYSHYHLGLLPDSEMTSHSQHSTATRQPSMTLQRAVSLEGEPR
  KVVLHKGSTGLGFNIVGGEDGEGIFVSFILAGGPADLSGELQRGDQILSVNGIDLRGASH
  EQAAAALKGAGQTVTIIAQYQPEDYARFEAKIHDLREQMMNHSMSSGSGSLRTNQKRSLY
  VRAMFDYDKSKDSGLPSQGLSFKYGDILHVINASDDEWWQARRVMLEGDSEEMGVIPSKR
  RVERKERARLKTVKFNAKPGVIDSKGSFNDKRKKSFIFSRKFPFYKNKEQSEQETSDPER
  GQEDLILSYEPVTRQEINYTRPVIILGPMKDRINDDLISEFPDKFGSCVPHTTRPKRDYE
  VDGRDYHFVISREQMEKDIQEHKFIEAGQYNDNLYGTSVQSVRFVAERGKHCILDVSGNA
  IKRLQVAQLYPIAIFIKPRSLEPLMEMNKRLTEEQAKKTYDRAIKLEQEFGEYFTAIVQG
  DTLEDIYNQCKLVIEEQSGPFIWIPSKEKL
• Function: Required for perception of chronic pain through NMDA receptor signaling. Regulates surface expression of NMDA receptors in dorsal horn neurons of the spinal cord. Interacts with the cytoplasmic tail of NMDA receptor subunits as well as inward rectifying potassium channels. Involved in regulation of synaptic stability at cholinergic synapses. Part of the postsynaptic protein scaffold of excitatory synapses.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Tight junction (hsa04530)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  Ras activation upon Ca2+ influx through NMDA receptor (R-HSA-442982)
  RAF/MAP kinase cascade (R-HSA-5673001)
  Neurexins and neuroligins (R-HSA-6794361)
  Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)
  Negative regulation of NMDA receptor-mediated neuronal transmission (R-HSA-9617324)
  Long-term potentiation (R-HSA-9620244)
  Unblocking of NMDA receptors, glutamate binding and activation (R-HSA-438066)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Posttranslational Modification	[1]
Amyloidosis	DISHTAI2	Strong	Biomarker	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[3]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[5]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[7]
Kidney neoplasm	DISBNZTN	Strong	Altered Expression	[8]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[11]
Osteosarcoma	DISLQ7E2	Strong	Genetic Variation	[10]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[7]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[12]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[13]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[14]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Genetic Variation	[15]
Melanoma	DIS1RRCY	Limited	Biomarker	[16]
Myopia	DISK5S60	Limited	Genetic Variation	[17]
Parkinson disease	DISQVHKL	Limited	Biomarker	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Disks large homolog 2 (DLG2).	[19]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Disks large homolog 2 (DLG2).	[21]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Disks large homolog 2 (DLG2).	[21]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Disks large homolog 2 (DLG2).	[22]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Disks large homolog 2 (DLG2).	[23]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Disks large homolog 2 (DLG2).	[21]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Disks large homolog 2 (DLG2).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Disks large homolog 2 (DLG2).	[24]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Disks large homolog 2 (DLG2).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Disks large homolog 2 (DLG2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Disks large homolog 2 (DLG2).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Disks large homolog 2 (DLG2).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Disks large homolog 2 (DLG2).	[28]

References

• [1] Crocin-protected malathion-induced spatial memory deficits by inhibiting TAU protein hyperphosphorylation and antiapoptotic effects.Nutr Neurosci. 2020 Mar;23(3):221-236. doi: 10.1080/1028415X.2018.1492772. Epub 2019 Feb 21.
• [2] PSD-93 Attenuates Amyloid--Mediated Cognitive Dysfunction by Promoting the Catabolism of Amyloid-.J Alzheimers Dis. 2017;59(3):913-927. doi: 10.3233/JAD-170320.
• [3] RasGRP1 promotes amphetamine-induced motor behavior through a Rhes interaction network ("Rhesactome") in the striatum.Sci Signal. 2016 Nov 15;9(454):ra111. doi: 10.1126/scisignal.aaf6670.
• [4] Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder.Brain Res. 2007 Jan 5;1127(1):108-18. doi: 10.1016/j.brainres.2006.09.011. Epub 2006 Nov 17.
• [5] A gene (DLG2) located at 17q12-q21 encodes a new homologue of the Drosophila tumor suppressor dIg-A.Genomics. 1995 Jul 1;28(1):25-31. doi: 10.1006/geno.1995.1101.
• [6] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [7] MicroRNA-23a depletion promotes apoptosis of ovarian cancer stem cell and inhibits cell migration by targeting DLG2.Cancer Biol Ther. 2019;20(6):897-911. doi: 10.1080/15384047.2019.1579960. Epub 2019 Mar 12.
• [8] Differential expression of a new isoform of DLG2 in renal oncocytoma.BMC Cancer. 2006 Apr 26;6:106. doi: 10.1186/1471-2407-6-106.
• [9] Abnormal striatal expression of transcripts encoding NMDA interacting PSD proteins in schizophrenia, bipolar disorder and major depression.Schizophr Res. 2005 Oct 1;78(1):87-93. doi: 10.1016/j.schres.2005.06.012.
• [10] Cross-species genomics identifies DLG2 as a tumor suppressor in osteosarcoma.Oncogene. 2019 Jan;38(2):291-298. doi: 10.1038/s41388-018-0444-4. Epub 2018 Aug 9.
• [11] An opposing function of paralogs in balancing developmental synapse maturation.PLoS Biol. 2018 Dec 26;16(12):e2006838. doi: 10.1371/journal.pbio.2006838. eCollection 2018 Dec.
• [12] Genome-wide association study of response to tumour necrosis factor inhibitor therapy in rheumatoid arthritis.Pharmacogenomics J. 2018 Sep;18(5):657-664. doi: 10.1038/s41397-018-0040-6. Epub 2018 Aug 31.
• [13] A genome-wide association study identifies susceptibility loci for Wilms tumor.Nat Genet. 2012 Apr 29;44(6):681-4. doi: 10.1038/ng.2251.
• [14] Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability.Genome Med. 2017 Jul 19;9(1):67. doi: 10.1186/s13073-017-0452-y.
• [15] A genome-wide association study of chronic obstructive pulmonary disease in Hispanics.Ann Am Thorac Soc. 2015 Mar;12(3):340-8. doi: 10.1513/AnnalsATS.201408-380OC.
• [16] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [17] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [18] DLG2, but not TMEM229B, GPNMB, and ITGA8 polymorphism, is associated with Parkinson's disease in a Taiwanese population.Neurobiol Aging. 2018 Apr;64:158.e1-158.e6. doi: 10.1016/j.neurobiolaging.2017.11.016. Epub 2017 Dec 8.
• [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.
• [20] 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.
• [21] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [22] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [23] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [26] 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.
• [27] 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.
• [28] 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.