Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9WY1QM)

• DOT Name: Multiple PDZ domain protein (MPDZ)
• Synonyms: Multi-PDZ domain protein 1
• Gene Name: MPDZ
• Related Disease:
  Alcohol use disorder
  Alcohol withdrawal
  Autism
  Autism spectrum disorder
  Clear cell renal carcinoma
  Communicating hydrocephalus
  Congenital hydrocephalus
  Hydrocephalus
  Hydrocephalus, nonsyndromic, autosomal recessive 2
  Keratoconus
  Neoplasm
  Pervasive developmental disorder
  Congenital hereditary endothelial dystrophy of cornea
  Heroin dependence
  Retinopathy
  Alcohol dependence
• UniProt ID: MPDZ_HUMAN
• PDB ID: 2FCF; 2FNE; 2IWN; 2IWO; 2IWP; 2IWQ; 2O2T; 2OPG; 2QG1
• Pfam ID: PF09045 ; PF16667 ; PF00595
• Sequence:
  MLEAIDKNRALHAAERLQTKLRERGDVANEDKLSLLKSVLQSPLFSQILSLQTSVQQLKD
  QVNIATSATSNIEYAHVPHLSPAVIPTLQNESFLLSPNNGNLEALTGPGIPHINGKPACD
  EFDQLIKNMAQGRHVEVFELLKPPSGGLGFSVVGLRSENRGELGIFVQEIQEGSVAHRDG
  RLKETDQILAINGQALDQTITHQQAISILQKAKDTVQLVIARGSLPQLVSPIVSRSPSAA
  STISAHSNPVHWQHMETIELVNDGSGLGFGIIGGKATGVIVKTILPGGVADQHGRLCSGD
  HILKIGDTDLAGMSSEQVAQVLRQCGNRVKLMIARGAIEERTAPTALGITLSSSPTSTPE
  LRVDASTQKGEESETFDVELTKNVQGLGITIAGYIGDKKLEPSGIFVKSITKSSAVEHDG
  RIQIGDQIIAVDGTNLQGFTNQQAVEVLRHTGQTVLLTLMRRGMKQEAELMSREDVTKDA
  DLSPVNASIIKENYEKDEDFLSSTRNTNILPTEEEGYPLLSAEIEEIEDAQKQEAALLTK
  WQRIMGINYEIVVAHVSKFSENSGLGISLEATVGHHFIRSVLPEGPVGHSGKLFSGDELL
  EVNGITLLGENHQDVVNILKELPIEVTMVCCRRTVPPTTQSELDSLDLCDIELTEKPHVD
  LGEFIGSSETEDPVLAMTDAGQSTEEVQAPLAMWEAGIQHIELEKGSKGLGFSILDYQDP
  IDPASTVIIIRSLVPGGIAEKDGRLLPGDRLMFVNDVNLENSSLEEAVEALKGAPSGTVR
  IGVAKPLPLSPEEGYVSAKEDSFLYPPHSCEEAGLADKPLFRADLALVGTNDADLVDEST
  FESPYSPENDSIYSTQASILSLHGSSCGDGLNYGSSLPSSPPKDVIENSCDPVLDLHMSL
  EELYTQNLLQRQDENTPSVDISMGPASGFTINDYTPANAIEQQYECENTIVWTESHLPSE
  VISSAELPSVLPDSAGKGSEYLLEQSSLACNAECVMLQNVSKESFERTINIAKGNSSLGM
  TVSANKDGLGMIVRSIIHGGAISRDGRIAIGDCILSINEESTISVTNAQARAMLRRHSLI
  GPDIKITYVPAEHLEEFKISLGQQSGRVMALDIFSSYTGRDIPELPEREEGEGEESELQN
  TAYSNWNQPRRVELWREPSKSLGISIVGGRGMGSRLSNGEVMRGIFIKHVLEDSPAGKNG
  TLKPGDRIVEVDGMDLRDASHEQAVEAIRKAGNPVVFMVQSIINRPRKSPLPSLLHNLYP
  KYNFSSTNPFADSLQINADKAPSQSESEPEKAPLCSVPPPPPSAFAEMGSDHTQSSASKI
  SQDVDKEDEFGYSWKNIRERYGTLTGELHMIELEKGHSGLGLSLAGNKDRSRMSVFIVGI
  DPNGAAGKDGRLQIADELLEINGQILYGRSHQNASSIIKCAPSKVKIIFIRNKDAVNQMA
  VCPGNAVEPLPSNSENLQNKETEPTVTTSDAAVDLSSFKNVQHLELPKDQGGLGIAISEE
  DTLSGVIIKSLTEHGVAATDGRLKVGDQILAVDDEIVVGYPIEKFISLLKTAKMTVKLTI
  HAENPDSQAVPSAAGAASGEKKNSSQSLMVPQSGSPEPESIRNTSRSSTPAIFASDPATC
  PIIPGCETTIEISKGRTGLGLSIVGGSDTLLGAIIIHEVYEEGAACKDGRLWAGDQILEV
  NGIDLRKATHDEAINVLRQTPQRVRLTLYRDEAPYKEEEVCDTLTIELQKKPGKGLGLSI
  VGKRNDTGVFVSDIVKGGIADADGRLMQGDQILMVNGEDVRNATQEAVAALLKCSLGTVT
  LEVGRIKAGPFHSERRPSQSSQVSEGSLSSFTFPLSGSSTSESLESSSKKNALASEIQGL
  RTVEMKKGPTDSLGISIAGGVGSPLGDVPIFIAMMHPTGVAAQTQKLRVGDRIVTICGTS
  TEGMTHTQAVNLLKNASGSIEMQVVAGGDVSVVTGHQQEPASSSLSFTGLTSSSIFQDDL
  GPPQCKSITLERGPDGLGFSIVGGYGSPHGDLPIYVKTVFAKGAASEDGRLKRGDQIIAV
  NGQSLEGVTHEEAVAILKRTKGTVTLMVLS
• Function: Member of the NMDAR signaling complex that may play a role in control of AMPAR potentiation and synaptic plasticity in excitatory synapses. Promotes clustering of HT2RC at the cell surface.
• Tissue Specificity: Expressed in heart, brain, placenta, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway: Tight junction (hsa04530)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alcohol use disorder	DISMB65Y	Strong	Biomarker	[1]
Alcohol withdrawal	DIS7INCX	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[3]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[4]
Communicating hydrocephalus	DIS33112	Strong	Genetic Variation	[5]
Congenital hydrocephalus	DIS7O6UL	Strong	Biomarker	[6]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[6]
Hydrocephalus, nonsyndromic, autosomal recessive 2	DISET7WL	Strong	Autosomal recessive	[7]
Keratoconus	DISOONXH	Strong	Genetic Variation	[8]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[9]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[3]
Congenital hereditary endothelial dystrophy of cornea	DISHLPKQ	moderate	Genetic Variation	[10]
Heroin dependence	DISQ1H57	moderate	Genetic Variation	[11]
Retinopathy	DISB4B0F	moderate	Biomarker	[12]
Alcohol dependence	DIS4ZSCO	Limited	Biomarker	[13]

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 Multiple PDZ domain protein (MPDZ).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Multiple PDZ domain protein (MPDZ).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Multiple PDZ domain protein (MPDZ).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Multiple PDZ domain protein (MPDZ).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Multiple PDZ domain protein (MPDZ).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Multiple PDZ domain protein (MPDZ).	[19]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Multiple PDZ domain protein (MPDZ).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Multiple PDZ domain protein (MPDZ).	[21]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Multiple PDZ domain protein (MPDZ).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Multiple PDZ domain protein (MPDZ).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Multiple PDZ domain protein (MPDZ).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Multiple PDZ domain protein (MPDZ).	[25]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Multiple PDZ domain protein (MPDZ).	[26]

References

• [1] Rostroventral caudate putamen involvement in ethanol withdrawal is influenced by a chromosome 4 locus.Genes Brain Behav. 2010 Oct;9(7):768-76. doi: 10.1111/j.1601-183X.2010.00611.x. Epub 2010 Sep 1.
• [2] Mpdz expression in the caudolateral substantia nigra pars reticulata is crucially involved in alcohol withdrawal.Genes Brain Behav. 2014 Nov;13(8):769-76. doi: 10.1111/gbb.12171. Epub 2014 Sep 17.
• [3] CASPR2 forms a complex with GPR37 via MUPP1 but not with GPR37(R558Q), an autism spectrum disorder-related mutation.J Neurochem. 2015 Aug;134(4):783-93. doi: 10.1111/jnc.13168. Epub 2015 Jun 3.
• [4] Copy number variations and expression of MPDZ are prognostic biomarkers for clear cell renal cell carcinoma.Oncotarget. 2017 Aug 12;8(45):78713-78725. doi: 10.18632/oncotarget.20220. eCollection 2017 Oct 3.
• [5] Compound heterozygous variants in the multiple PDZ domain protein (MPDZ) cause a case of mild non-progressive communicating hydrocephalus.BMC Med Genet. 2018 Mar 2;19(1):34. doi: 10.1186/s12881-018-0540-x.
• [6] Murine MPDZ-linked hydrocephalus is caused by hyperpermeability of the choroid plexus.EMBO Mol Med. 2019 Jan;11(1):e9540. doi: 10.15252/emmm.201809540.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] Analysis of multiple genetic loci reveals MPDZ-NF1B rs1324183 as a putative genetic marker for keratoconus.Br J Ophthalmol. 2018 Dec;102(12):1736-1741. doi: 10.1136/bjophthalmol-2018-312218. Epub 2018 Jul 12.
• [9] MPDZ promotes DLL4-induced Notch signaling during angiogenesis.Elife. 2018 Apr 5;7:e32860. doi: 10.7554/eLife.32860.
• [10] Observation of nine previously reported and 10 non-reported SLC4A11 mutations among 20 Iranian CHED probands and identification of an MPDZ mutation as possible cause of CHED and FECD in one family.Br J Ophthalmol. 2020 Nov;104(11):1621-1628. doi: 10.1136/bjophthalmol-2019-314377. Epub 2019 Aug 16.
• [11] Synaptic Plasticity and Signal Transduction Gene Polymorphisms and Vulnerability to Drug Addictions in Populations of European or African Ancestry.CNS Neurosci Ther. 2015 Nov;21(11):898-904. doi: 10.1111/cns.12450. Epub 2015 Sep 19.
• [12] Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa.Invest Ophthalmol Vis Sci. 2011 Sep 27;52(10):7432-40. doi: 10.1167/iovs.11-7872.
• [13] Novel MPDZ/MUPP1 transgenic and knockdown models confirm Mpdz's role in ethanol withdrawal and support its role in voluntary ethanol consumption.Addict Biol. 2015 Jan;20(1):143-7. doi: 10.1111/adb.12087. Epub 2013 Oct 10.
• [14] 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.
• [15] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [16] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [21] 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.
• [22] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [23] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [24] 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.
• [25] 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.
• [26] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.