Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPB1RGK)

• DOT Name: Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1)
• Synonyms: Guanine nucleotide-binding protein G(o) subunit alpha
• Gene Name: GNAO1
• Related Disease:
  Infantile spasm
  Movement disorder
  Developmental and epileptic encephalopathy, 17
  Neurodevelopmental disorder with involuntary movements
• UniProt ID: GNAO_HUMAN
• PDB ID: 6FUF; 6G79; 6K41; 6OIK; 6WWZ; 7D76; 7D77; 7EJ0; 7EJ8; 7EJA; 7EJK; 7QVM; 7T8X; 7T90; 7T94; 7T96; 7W2Z; 7W6P; 7W7E; 7XJJ; 7Y24; 8DZQ; 8E9X; 8FN1; 8HPT; 8HQC; 8I95; 8I97; 8I9L; 8I9S; 8IA2; 8J6D; 8JZZ
• Pfam ID: PF00503
• Sequence:
  MGCTLSAEERAALERSKAIEKNLKEDGISAAKDVKLLLLGAGESGKSTIVKQMKIIHEDG
  FSGEDVKQYKPVVYSNTIQSLAAIVRAMDTLGIEYGDKERKADAKMVCDVVSRMEDTEPF
  SAELLSAMMRLWGDSGIQECFNRSREYQLNDSAKYYLDSLDRIGAADYQPTEQDILRTRV
  KTTGIVETHFTFKNLHFRLFDVGGQRSERKKWIHCFEDVTAIIFCVALSGYDQVLHEDET
  TNRMHESLMLFDSICNNKFFIDTSIILFLNKKDLFGEKIKKSPLTICFPEYTGPNTYEDA
  AAYIQAQFESKNRSPNKEIYCHMTCATDTNNIQVVFDAVTDIIIANNLRGCGLY
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(o) protein function is not clear. Stimulated by RGS14.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Circadian entrainment (hsa04713)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  GABAergic sy.pse (hsa04727)
  Dopaminergic sy.pse (hsa04728)
  Long-term depression (hsa04730)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Oxytocin sig.ling pathway (hsa04921)
  Relaxin sig.ling pathway (hsa04926)
  Morphine addiction (hsa05032)
  Alcoholism (hsa05034)
  Chagas disease (hsa05142)
  Toxoplasmosis (hsa05145)
  Human cytomegalovirus infection (hsa05163)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway: Ca2+ pathway (R-HSA-4086398)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile spasm	DISZSKDG	Definitive	Autosomal dominant	[1]
Movement disorder	DISOJJ2D	Definitive	Autosomal dominant	[1]
Developmental and epileptic encephalopathy, 17	DISUI6PS	Strong	Autosomal dominant	[2]
Neurodevelopmental disorder with involuntary movements	DISEE2GF	Strong	Autosomal dominant	[3]

11 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 Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[10]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[11]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[15]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1).	[12]

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] De Novo mutations in GNAO1, encoding a Go subunit of heterotrimeric G proteins, cause epileptic encephalopathy. Am J Hum Genet. 2013 Sep 5;93(3):496-505. doi: 10.1016/j.ajhg.2013.07.014. Epub 2013 Aug 29.
• [3] Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. Hum Mutat. 2017 Feb;38(2):216-225. doi: 10.1002/humu.23149. Epub 2016 Dec 9.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] 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.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] 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.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [12] 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.
• [13] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [14] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [15] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [16] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.