Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ5YBO8)

• DOT Name: Glutamate receptor ionotropic, NMDA 1 (GRIN1)
• Synonyms: GluN1; Glutamate receptor subunit zeta-1; N-methyl-D-aspartate receptor subunit NR1; NMD-R1
• Gene Name: GRIN1
• Related Disease:
  Complex neurodevelopmental disorder
  Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive
  Developmental and epileptic encephalopathy 101
  Intellectual disability, autosomal dominant 8
  Autosomal dominant non-syndromic intellectual disability
• UniProt ID: NMDZ1_HUMAN
• PDB ID: 2HQW ; 2NR1 ; 3BYA ; 5H8F ; 5H8H ; 5H8N ; 5H8Q ; 5I2K ; 5I2N ; 5KCJ ; 5KDT ; 5TP9 ; 5TPA ; 6IRA ; 6IRF ; 6IRG ; 6IRH ; 7EOQ ; 7EOR ; 7EOS ; 7EOT ; 7EOU ; 7EU7 ; 7EU8 ; 7YFF ; 7YFL ; 7YFM ; 7YFO ; 7YFR ; 8E92 ; 8E93 ; 8E94 ; 8E96 ; 8E97 ; 8E98 ; 8E99
• Pfam ID: PF01094 ; PF00060 ; PF10613 ; PF00497
• Sequence:
  MSTMRLLTLALLFSCSVARAACDPKIVNIGAVLSTRKHEQMFREAVNQANKRHGSWKIQL
  NATSVTHKPNAIQMALSVCEDLISSQVYAILVSHPPTPNDHFTPTPVSYTAGFYRIPVLG
  LTTRMSIYSDKSIHLSFLRTVPPYSHQSSVWFEMMRVYSWNHIILLVSDDHEGRAAQKRL
  ETLLEERESKAEKVLQFDPGTKNVTALLMEAKELEARVIILSASEDDAATVYRAAAMLNM
  TGSGYVWLVGEREISGNALRYAPDGILGLQLINGKNESAHISDAVGVVAQAVHELLEKEN
  ITDPPRGCVGNTNIWKTGPLFKRVLMSSKYADGVTGRVEFNEDGDRKFANYSIMNLQNRK
  LVQVGIYNGTHVIPNDRKIIWPGGETEKPRGYQMSTRLKIVTIHQEPFVYVKPTLSDGTC
  KEEFTVNGDPVKKVICTGPNDTSPGSPRHTVPQCCYGFCIDLLIKLARTMNFTYEVHLVA
  DGKFGTQERVNNSNKKEWNGMMGELLSGQADMIVAPLTINNERAQYIEFSKPFKYQGLTI
  LVKKEIPRSTLDSFMQPFQSTLWLLVGLSVHVVAVMLYLLDRFSPFGRFKVNSEEEEEDA
  LTLSSAMWFSWGVLLNSGIGEGAPRSFSARILGMVWAGFAMIIVASYTANLAAFLVLDRP
  EERITGINDPRLRNPSDKFIYATVKQSSVDIYFRRQVELSTMYRHMEKHNYESAAEAIQA
  VRDNKLHAFIWDSAVLEFEASQKCDLVTTGELFFRSGFGIGMRKDSPWKQNVSLSILKSH
  ENGFMEDLDKTWVRYQECDSRSNAPATLTFENMAGVFMLVAGGIVAGIFLIFIEIAYKRH
  KDARRKQMQLAFAAVNVWRKNLQDRKSGRAEPDPKKKATFRAITSTLASSFKRRRSSKDT
  STGGGRGALQNQKDTVLPRRAIEREEGQLQLCSRHRES
• Function: Component of NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+). Sensitivity to glutamate and channel kinetics depend on the subunit composition.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Glutamatergic sy.pse (hsa04724)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Nicotine addiction (hsa05033)
  Alcoholism (hsa05034)
• Reactome Pathway:
  Unblocking of NMDA receptors, glutamate binding and activation (R-HSA-438066)
  Ras activation upon Ca2+ influx through NMDA receptor (R-HSA-442982)
  RAF/MAP kinase cascade (R-HSA-5673001)
  Neurexins and neuroligins (R-HSA-6794361)
  Synaptic adhesion-like molecules (R-HSA-8849932)
  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)
  EPHB-mediated forward signaling (R-HSA-3928662)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal recessive	[1]
Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive	DISOX9TO	Definitive	Autosomal recessive	[2]
Developmental and epileptic encephalopathy 101	DIS9Z9TQ	Strong	Autosomal recessive	[3]
Intellectual disability, autosomal dominant 8	DISAB1QF	Strong	Autosomal dominant	[4]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[10]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[11]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[8]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[8]
Imipramine	DM2NUH3	Approved	Imipramine decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[8]
Gabapentin	DM6T924	Approved	Gabapentin decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[8]
Sulfadiazine	DMTW3R8	Approved	Sulfadiazine decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[8]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[8]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[8]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[8]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[8]
HYDRAZINECARBOXAMIDE	DMARWG5	Investigative	HYDRAZINECARBOXAMIDE decreases the activity of Glutamate receptor ionotropic, NMDA 1 (GRIN1).	[14]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy. Eur J Hum Genet. 2017 Feb;25(3):376-380. doi: 10.1038/ejhg.2016.163. Epub 2017 Jan 4.
• [3] Novel genetic causes for cerebral visual impairment. Eur J Hum Genet. 2016 May;24(5):660-5. doi: 10.1038/ejhg.2015.186. Epub 2015 Sep 9.
• [4] Ablation of NMDA receptors enhances the excitability of hippocampal CA3 neurons. PLoS One. 2009;4(1):e3993. doi: 10.1371/journal.pone.0003993. Epub 2009 Jan 14.
• [5] Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet. 2011 Mar 11;88(3):306-16. doi: 10.1016/j.ajhg.2011.02.001. Epub 2011 Mar 3.
• [6] 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.
• [7] All-trans-retinoic acid induces manganese superoxide dismutase in human neuroblastoma through NF-kappaB. Free Radic Biol Med. 2008 Apr 15;44(8):1610-6. doi: 10.1016/j.freeradbiomed.2008.01.015. Epub 2008 Jan 30.
• [8] Establishment of a 13 genes-based molecular prediction score model to discriminate the neurotoxic potential of food relevant-chemicals. Toxicol Lett. 2022 Feb 1;355:1-18. doi: 10.1016/j.toxlet.2021.10.013. Epub 2021 Nov 5.
• [9] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Cocaine-induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non-human primates. J Neurochem. 2005 Dec;95(6):1785-93. doi: 10.1111/j.1471-4159.2005.03517.x.
• [12] Genistein disrupts glucocorticoid receptor signaling in human uterine endometrial Ishikawa cells. Environ Health Perspect. 2015 Jan;123(1):80-7. doi: 10.1289/ehp.1408437. Epub 2014 Aug 19.
• [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] The food contaminant semicarbazide acts as an endocrine disrupter: Evidence from an integrated in vivo/in vitro approach. Chem Biol Interact. 2010 Jan 5;183(1):40-8. doi: 10.1016/j.cbi.2009.09.016.