Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE0KX9F)

• DOT Name: Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1)
• Synonyms: Adenylate cyclase-inhibiting G alpha protein
• Gene Name: GNAI1
• Related Disease:
  Complex neurodevelopmental disorder
  Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities
• UniProt ID: GNAI1_HUMAN
• PDB ID: 1KJY ; 1Y3A ; 2G83 ; 2GTP ; 2IK8 ; 2OM2 ; 2XNS ; 3ONW ; 3QE0 ; 3QI2 ; 3UMR ; 3UMS ; 4G5Q ; 5JS7 ; 5JS8 ; 5TDH ; 6CMO ; 6CRK ; 6DDE ; 6DDF ; 6KPF ; 6KPG ; 6LFM ; 6LFO ; 6LML ; 6N4B ; 6OMM ; 6OS9 ; 6OSA ; 6OT0 ; 6PB0 ; 6PB1 ; 6PT0 ; 6QNO ; 6VU8 ; 6XBJ ; 6XBK ; 6XBL ; 6XBM ; 7CMU ; 7CMV ; 7DB6 ; 7DW9 ; 7E2X ; 7E2Y ; 7E2Z ; 7E32 ; 7E33 ; 7E9G ; 7EB2 ; 7EJX ; 7EO2 ; 7EO4 ; 7EUO ; 7EVY ; 7EVZ ; 7EW0 ; 7EW1 ; 7EW2 ; 7EW3 ; 7EW4 ; 7EW7 ; 7EXD ; 7EZH ; 7EZK ; 7EZM ; 7F1Q ; 7F1R ; 7F1S ; 7F4D ; 7F4F ; 7F4H ; 7F4I ; 7JHJ ; 7JVR ; 7L0P ; 7L0Q ; 7L0R ; 7L0S ; 7MTS ; 7NA7 ; 7NA8 ; 7O7F ; 7P02 ; 7RKM ; 7RKN ; 7RKX ; 7RKY ; 7S8M ; 7S8O ; 7SBF ; 7SCG ; 7SQO ; 7T2G ; 7T2H ; 7T6B ; 7T6S ; 7T6T ; 7T6U ; 7T6V ; 7TRK ; 7TRP ; 7TRQ ; 7TRS ; 7TUZ ; 7U2K ; 7U2L ; 7V68 ; 7V69 ; 7V6A ; 7V9L ; 7VAB ; 7VDH ; 7VDL ; 7VDM ; 7VFX ; 7VGX ; 7VGY ; 7VGZ ; 7VH0 ; 7VIE ; 7VIF ; 7VIG ; 7VIH ; 7VKT ; 7VL8 ; 7VL9 ; 7VLA ; 7VUG ; 7VUY ; 7VUZ ; 7VV3 ; 7VV5 ; 7W0L ; 7W0M ; 7W0N ; 7W0O ; 7W0P ; 7WF7 ; 7WIC ; 7WIG ; 7WJ5 ; 7WQ3 ; 7WU4 ; 7WU5 ; 7WU9 ; 7WUI ; 7WUJ ; 7WVU ; 7WYB ; 7WZ4 ; 7X2V ; 7X5H ; 7X9A ; 7X9B ; 7X9C ; 7X9Y ; 7XA3 ; 7XAT ; 7XAU ; 7XAV ; 7XBW ; 7XBX ; 7XK2 ; 7XK8 ; 7XMR ; 7XMS ; 7XMT ; 7XTA ; 7XXH ; 7Y12 ; 7Y15 ; 7Y1F ; 7Y64 ; 7Y65 ; 7Y66 ; 7Y67 ; 7Y89 ; 7YAC ; 7YAE ; 7YDJ ; 7YDP ; 7YKD ; 7YON ; 7YOO ; 7YU3 ; 7YU5 ; 7YU6 ; 7YU7 ; 7YU8 ; 8DZP ; 8EF5 ; 8EF6 ; 8EFB ; 8EFL ; 8EFO ; 8EFQ ; 8F7Q ; 8F7R ; 8F7S ; 8F7W ; 8F7X ; 8FEG ; 8G05 ; 8G59 ; 8G94 ; 8GHV ; 8GUQ ; 8GUR ; 8GUS ; 8GUT ; 8H2G ; 8H4I ; 8HBD ; 8HK2 ; 8HK3 ; 8HK5 ; 8HNK ; 8HNL ; 8HNM ; 8HQE ; 8HQM ; 8HQN ; 8HS3 ; 8HSC ; 8HVI ; 8IA8 ; 8IC0 ; 8ID3 ; 8ID4 ; 8ID6 ; 8ID8 ; 8ID9 ; 8IHB ; 8IHF ; 8IHH ; 8IHI ; 8IHJ ; 8INR ; 8IOC ; 8IOD ; 8IRS ; 8IRT ; 8IRV ; 8IW4 ; 8IW7 ; 8IW9 ; 8IY5 ; 8J18 ; 8J19 ; 8J1A ; 8J6P ; 8J6Q ; 8J6R ; 8JD3 ; 8JD5 ; 8JHY ; 8JII ; 8JIL ; 8JIM ; 8JR9 ; 8JSP ; 8JZ7 ; 8K2X ; 8K4N ; 8SAI ; 8SG1 ; 8W8B ; 8WRB
• Pfam ID: PF00503
• Sequence:
  MGCTLSAEDKAAVERSKMIDRNLREDGEKAAREVKLLLLGAGESGKSTIVKQMKIIHEAG
  YSEEECKQYKAVVYSNTIQSIIAIIRAMGRLKIDFGDSARADDARQLFVLAGAAEEGFMT
  AELAGVIKRLWKDSGVQACFNRSREYQLNDSAAYYLNDLDRIAQPNYIPTQQDVLRTRVK
  TTGIVETHFTFKDLHFKMFDVGGQRSERKKWIHCFEGVTAIIFCVALSDYDLVLAEDEEM
  NRMHESMKLFDSICNNKWFTDTSIILFLNKKDLFEEKIKKSPLTICYPEYAGSNTYEEAA
  AYIQCQFEDLNKRKDTKEIYTHFTCATDTKNVQFVFDAVTDVIIKNNLKDCGLF
• Function: Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal. Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins. Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. Required for normal cytokinesis during mitosis. Required for cortical dynein-dynactin complex recruitment during metaphase.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Chemokine sig.ling pathway (hsa04062)
  Sphingolipid sig.ling pathway (hsa04071)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Axon guidance (hsa04360)
  Apelin sig.ling pathway (hsa04371)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Leukocyte transendothelial migration (hsa04670)
  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)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Oxytocin sig.ling pathway (hsa04921)
  Regulation of lipolysis in adipocytes (hsa04923)
  Renin secretion (hsa04924)
  Relaxin sig.ling pathway (hsa04926)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Gastric acid secretion (hsa04971)
  Parkinson disease (hsa05012)
  Cocaine addiction (hsa05030)
  Morphine addiction (hsa05032)
  Alcoholism (hsa05034)
  Pertussis (hsa05133)
  Chagas disease (hsa05142)
  Toxoplasmosis (hsa05145)
  Human cytomegalovirus infection (hsa05163)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  ADP signalling through P2Y purinoceptor 12 (R-HSA-392170)
  Adrenaline,noradrenaline inhibits insulin secretion (R-HSA-400042)
  G alpha (s) signalling events (R-HSA-418555)
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  Regulation of insulin secretion (R-HSA-422356)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  GPER1 signaling (R-HSA-9634597)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  Adenylate cyclase inhibitory pathway (R-HSA-170670)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities	DIS2M0VZ	Strong	Autosomal dominant	[2]

16 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(i) subunit alpha-1 (GNAI1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[9]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[4]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[12]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1).	[16]

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] Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017 Feb 23;542(7642):433-438. doi: 10.1038/nature21062. Epub 2017 Jan 25.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [9] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [10] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [14] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.