Details of Drug Off-Target (DOT)

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

• DOT Name: Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ)
• Synonyms: Guanine nucleotide-binding protein alpha-q
• Gene Name: GNAQ
• Related Disease: Sturge-Weber syndrome
• UniProt ID: GNAQ_HUMAN
• PDB ID: 6VU5; 7EZM; 7F6G; 7F6H; 7F6I; 7F8W; 7W3Z; 7W40; 7XOW; 8G59; 8IA7; 8IYS; 8JPB; 8JPC; 8JPE; 8UQN; 8UQO
• Pfam ID: PF00503
• Sequence:
  MTLESIMACCLSEEAKEARRINDEIERQLRRDKRDARRELKLLLLGTGESGKSTFIKQMR
  IIHGSGYSDEDKRGFTKLVYQNIFTAMQAMIRAMDTLKIPYKYEHNKAHAQLVREVDVEK
  VSAFENPYVDAIKSLWNDPGIQECYDRRREYQLSDSTKYYLNDLDRVADPAYLPTQQDVL
  RVRVPTTGIIEYPFDLQSVIFRMVDVGGQRSERRKWIHCFENVTSIMFLVALSEYDQVLV
  ESDNENRMEESKALFRTIITYPWFQNSSVILFLNKKDLLEEKIMYSHLVDYFPEYDGPQR
  DAQAAREFILKMFVDLNPDSDKIIYSHFTCATDTENIRFVFAAVKDTILQLNLKEYNLV
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Required for platelet activation. Regulates B-cell selection and survival and is required to prevent B-cell-dependent autoimmunity. Regulates chemotaxis of BM-derived neutrophils and dendritic cells (in vitro). Transduces FFAR4 signaling in response to long-chain fatty acids (LCFAs). Together with GNA11, required for heart development.
• Tissue Specificity: Predominantly expressed in ovary, prostate, testis and colon. Down-regulated in the peripheral blood lymphocytes (PBLs) of rheumatoid arthritis patients (at protein level).
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Chemokine sig.ling pathway (hsa04062)
  Sphingolipid sig.ling pathway (hsa04071)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Apelin sig.ling pathway (hsa04371)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  Dopaminergic sy.pse (hsa04728)
  Long-term depression (hsa04730)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin secretion (hsa04911)
  GnRH sig.ling pathway (hsa04912)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Thyroid hormone synthesis (hsa04918)
  Oxytocin sig.ling pathway (hsa04921)
  Glucagon sig.ling pathway (hsa04922)
  Renin secretion (hsa04924)
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  GnRH secretion (hsa04929)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Alzheimer disease (hsa05010)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Yersinia infection (hsa05135)
  Chagas disease (hsa05142)
  African trypanosomiasis (hsa05143)
  Amoebiasis (hsa05146)
  Human cytomegalovirus infection (hsa05163)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G-protein activation (R-HSA-202040)
  Acetylcholine regulates insulin secretion (R-HSA-399997)
  G alpha (q) signalling events (R-HSA-416476)
  ADP signalling through P2Y purinoceptor 1 (R-HSA-418592)
  Thromboxane signalling through TP receptor (R-HSA-428930)
  Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion (R-HSA-434316)
  Thrombin signalling through proteinase activated receptors (PARs) (R-HSA-456926)
  Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding (R-HSA-6814122)
  PLC beta mediated events (R-HSA-112043)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Sturge-Weber syndrome	DISL0WMD	Strong	Autosomal dominant	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) increases the Thrombosis ADR of Ciclosporin.	[13]
Trametinib	DM2JGQ3	Approved	Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) increases the response to substance of Trametinib.	[14]
(+)-JQ1	DM1CZSJ	Phase 1	Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) increases the response to substance of (+)-JQ1.	[15]

12 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 Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[6]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[7]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[8]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[3]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[10]
Sphingosine-1-Phosphate	DMJCQKA	Phase 1	Sphingosine-1-Phosphate increases the expression of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[12]

1 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 increases the methylation of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ).	[9]

References

• [1] Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013 May 23;368(21):1971-9. doi: 10.1056/NEJMoa1213507. Epub 2013 May 8.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] 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.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] A natural piper-amide-like compound NED-135 exhibits a potent inhibitory effect on the invasive breast cancer cells. Chem Biol Interact. 2015 Jul 25;237:58-65. doi: 10.1016/j.cbi.2015.05.006. Epub 2015 May 14.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [13] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [14] Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner. Clin Cancer Res. 2012 Aug 15;18(16):4345-55. doi: 10.1158/1078-0432.CCR-11-3227. Epub 2012 Jun 25.
• [15] BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells. Oncotarget. 2015 Oct 20;6(32):33397-409. doi: 10.18632/oncotarget.5179.