Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT958HK1)

• DOT Name: Glutamate receptor-interacting protein 1 (GRIP1)
• Synonyms: GRIP-1
• Gene Name: GRIP1
• Related Disease:
  Autism
  Fraser syndrome 3
  Advanced cancer
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Bipolar disorder
  Disorder of orbital region
  Eye disorder
  Fraser syndrome 1
  Major depressive disorder
  Polydactyly
  Dystrophic epidermolysis bullosa
  Recessive dystrophic epidermolysis bullosa
  Fraser syndrome
  Carcinoma of liver and intrahepatic biliary tract
  Chronic kidney disease
  Dengue
  Liver cancer
• UniProt ID: GRIP1_HUMAN
• PDB ID: 2JIL
• Pfam ID: PF00595 ; PF17820
• Sequence:
  MIAVSFKCRCQILRRLTKDESPYTKSASQTKPPDGALAVRRQSIPEEFKGSTVVELMKKE
  GTTLGLTVSGGIDKDGKPRVSNLRQGGIAARSDQLDVGDYIKAVNGINLAKFRHDEIISL
  LKNVGERVVLEVEYELPPVSVQGSSVIFRTVEVTLHKEGNTFGFVIRGGAHDDRNKSRPV
  VITCVRPGGPADREGTIKPGDRLLSVDGIRLLGTTHAEAMSILKQCGQEAALLIEYDVSV
  MDSVATASGPLLVEVAKTPGASLGVALTTSMCCNKQVIVIDKIKSASIADRCGALHVGDH
  ILSIDGTSMEYCTLAEATQFLANTTDQVKLEILPHHQTRLALKGPDHVKIQRSDRQLTWD
  SWASNHSSLHTNHHYNTYHPDHCRVPALTFPKAPPPNSPPALVSSSFSPTSMSAYSLSSL
  NMGTLPRSLYSTSPRGTMMRRRLKKKDFKSSLSLASSTVGLAGQVVHTETTEVVLTADPV
  TGFGIQLQGSVFATETLSSPPLISYIEADSPAERCGVLQIGDRVMAINGIPTEDSTFEEA
  SQLLRDSSITSKVTLEIEFDVAESVIPSSGTFHVKLPKKHNVELGITISSPSSRKPGDPL
  VISDIKKGSVAHRTGTLELGDKLLAIDNIRLDNCSMEDAVQILQQCEDLVKLKIRKDEDN
  SDEQESSGAIIYTVELKRYGGPLGITISGTEEPFDPIIISSLTKGGLAERTGAIHIGDRI
  LAINSSSLKGKPLSEAIHLLQMAGETVTLKIKKQTDAQSASSPKKFPISSHLSDLGDVEE
  DSSPAQKPGKLSDMYPSTVPSVDSAVDSWDGSAIDTSYGTQGTSFQASGYNFNTYDWRSP
  KQRGSLSPVTKPRSQTYPDVGLSYEDWDRSTASGFAGAADSAETEQEENFWSQALEDLET
  CGQSGILRELEEKADRRVSLRNMTLLATIMSGSTMSLNHEAPTPRSQLGRQASFQERSSS
  RPHYSQTTRSNTLPSDVGRKSVTLRKMKQEIKEIMSPTPVELHKVTLYKDSDMEDFGFSV
  ADGLLEKGVYVKNIRPAGPGDLGGLKPYDRLLQVNHVRTRDFDCCLVVPLIAESGNKLDL
  VISRNPLASQKSIDQQSLPGDWSEQNSAFFQQPSHGGNLETREPTNTL
• Function: May play a role as a localized scaffold for the assembly of a multiprotein signaling complex and as mediator of the trafficking of its binding partners at specific subcellular location in neurons. Through complex formation with NSG1, GRIA2 and STX12 controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting.
• Reactome Pathway: Trafficking of GluR2-containing AMPA receptors (R-HSA-416993)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Biomarker	[1]
Fraser syndrome 3	DISVSJDA	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[5]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[6]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[7]
Eye disorder	DISB52BH	Strong	Biomarker	[8]
Fraser syndrome 1	DISOH38D	Strong	Autosomal recessive	[7]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Polydactyly	DIS25BMZ	Strong	Biomarker	[9]
Dystrophic epidermolysis bullosa	DISALMGH	moderate	Biomarker	[10]
Recessive dystrophic epidermolysis bullosa	DISVOPLZ	moderate	Biomarker	[10]
Fraser syndrome	DISCLC2B	Supportive	Autosomal recessive	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[11]
Chronic kidney disease	DISW82R7	Limited	Genetic Variation	[12]
Dengue	DISKH221	Limited	Genetic Variation	[13]
Liver cancer	DISDE4BI	Limited	Biomarker	[11]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Glutamate receptor-interacting protein 1 (GRIP1) affects the response to substance of Estradiol.	[22]
Amiloride	DMRTSGP	Approved	Glutamate receptor-interacting protein 1 (GRIP1) affects the response to substance of Amiloride.	[22]

6 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 Glutamate receptor-interacting protein 1 (GRIP1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Glutamate receptor-interacting protein 1 (GRIP1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Glutamate receptor-interacting protein 1 (GRIP1).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Glutamate receptor-interacting protein 1 (GRIP1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glutamate receptor-interacting protein 1 (GRIP1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Glutamate receptor-interacting protein 1 (GRIP1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Glutamate receptor-interacting protein 1 (GRIP1).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Glutamate receptor-interacting protein 1 (GRIP1).	[21]

References

• [1] Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum.Neurobiol Dis. 2019 Dec;132:104602. doi: 10.1016/j.nbd.2019.104602. Epub 2019 Aug 30.
• [2] 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.
• [3] Randomised controlled trial protocol (GRIP study): examining the effect of involvement of a general practitioner and home care oncology nurse after a cancer diagnosis on patient reported outcomes and healthcare utilization.BMC Cancer. 2018 Feb 5;18(1):132. doi: 10.1186/s12885-018-4005-6.
• [4] Structural insight into GRIP1-PDZ6 in Alzheimer's disease: study from protein expression data to molecular dynamics simulations.J Biomol Struct Dyn. 2017 Aug;35(10):2235-2247. doi: 10.1080/07391102.2016.1214085. Epub 2016 Aug 1.
• [5] Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis.Nat Genet. 2013 Jun;45(6):697-700. doi: 10.1038/ng.2627. Epub 2013 Apr 28.
• [6] Genetic relationships between suicide attempts, suicidal ideation and major psychiatric disorders: a genome-wide association and polygenic scoring study.Am J Med Genet B Neuropsychiatr Genet. 2014 Jul;165B(5):428-37. doi: 10.1002/ajmg.b.32247. Epub 2014 Jun 25.
• [7] Mutations in GRIP1 cause Fraser syndrome. J Med Genet. 2012 May;49(5):303-6. doi: 10.1136/jmedgenet-2011-100590. Epub 2012 Apr 17.
• [8] Complex translocation t(1;12;14)(q42;q14;q32) and HMGA2 deletion in a fetus presenting growth delay and bilateral cataracts.Eur J Med Genet. 2015 Nov;58(11):591-6. doi: 10.1016/j.ejmg.2015.09.006. Epub 2015 Sep 16.
• [9] Fraser syndrome due to mutations in GRIP1--clinical phenotype in two families and expansion of the mutation spectrum.Am J Med Genet A. 2014 Mar;164A(3):837-40. doi: 10.1002/ajmg.a.36343. Epub 2013 Dec 19.
• [10] Epidermolysis bullosa and embryonic lethality in mice lacking the multi-PDZ domain protein GRIP1.Proc Natl Acad Sci U S A. 2002 May 14;99(10):6816-21. doi: 10.1073/pnas.092130099. Epub 2002 Apr 30.
• [11] Loss of NR2E3 represses AHR by LSD1 reprogramming, is associated with poor prognosis in liver cancer.Sci Rep. 2017 Sep 6;7(1):10662. doi: 10.1038/s41598-017-11106-2.
• [12] Genome-wide association and functional follow-up reveals new loci for kidney function.PLoS Genet. 2012;8(3):e1002584. doi: 10.1371/journal.pgen.1002584. Epub 2012 Mar 29.
• [13] Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome.PLoS Negl Trop Dis. 2018 Feb 15;12(2):e0006202. doi: 10.1371/journal.pntd.0006202. eCollection 2018 Feb.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] 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.
• [19] Bisphenol-A exposure induced neurotoxicity in glutamatergic neurons derived from human embryonic stem cells. Environ Int. 2019 Jun;127:324-332.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] 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.
• [22] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.