Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1H0ZXC)

• DOT Name: Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4)
• Gene Name: CHRNA4
• Related Disease:
  Autosomal dominant nocturnal frontal lobe epilepsy 1
  Sleep-related hypermotor epilepsy
  Autosomal dominant nocturnal frontal lobe epilepsy
• UniProt ID: ACHA4_HUMAN
• PDB ID: 2LLY; 5KXI; 6CNJ; 6CNK; 6UR8; 6USF
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MELGGPGAPRLLPPLLLLLGTGLLRASSHVETRAHAEERLLKKLFSGYNKWSRPVANISD
  VVLVRFGLSIAQLIDVDEKNQMMTTNVWVKQEWHDYKLRWDPADYENVTSIRIPSELIWR
  PDIVLYNNADGDFAVTHLTKAHLFHDGRVQWTPPAIYKSSCSIDVTFFPFDQQNCTMKFG
  SWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIR
  RLPLFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTS
  LVIPLIGEYLLFTMIFVTLSIVITVFVLNVHHRSPRTHTMPTWVRRVFLDIVPRLLLMKR
  PSVVKDNCRRLIESMHKMASAPRFWPEPEGEPPATSGTQSLHPPSPSFCVPLDVPAEPGP
  SCKSPSDQLPPQQPLEAEKASPHPSPGPCRPPHGTQAPGLAKARSLSVQHMSSPGEAVEG
  GVRCRSRSIQYCVPRDDAAPEADGQAAGALASRNTHSAELPPPDQPSPCKCTCKKEPSSV
  SPSATVKTRSTKAPPPHLPLSPALTRAVEGVQYIADHLKAEDTDFSVKEDWKYVAMVIDR
  IFLWMFIIVCLLGTVGLFLPPWLAGMI
• Function: After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodium ions.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Cholinergic sy.pse (hsa04725)
  Nicotine addiction (hsa05033)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  Highly calcium permeable postsynaptic nicotinic acetylcholine receptors (R-HSA-629594)
  Highly calcium permeable nicotinic acetylcholine receptors (R-HSA-629597)
  Highly sodium permeable postsynaptic acetylcholine nicotinic receptors (R-HSA-629587)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant nocturnal frontal lobe epilepsy 1	DISNEMUO	Definitive	Autosomal dominant	[1]
Sleep-related hypermotor epilepsy	DISWP477	Definitive	Autosomal dominant	[2]
Autosomal dominant nocturnal frontal lobe epilepsy	DISE3C4O	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[14]

9 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol affects the binding of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the binding of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[7]
Atropine	DMEN6X7	Approved	Atropine affects the binding of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[11]
Rivastigmine	DMG629M	Approved	Rivastigmine affects the binding of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[11]
Scopolamine	DMOM8AL	Approved	Scopolamine affects the binding of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[11]
Galantamine	DMEO794	Approved	Galantamine affects the binding of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[11]
CYTISINE	DMUF0BJ	Phase 3	CYTISINE affects the binding of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[13]
Physostigmine	DM2N0TO	Discontinued in Phase 2	Physostigmine affects the binding of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[11]
ABT-089	DM8DT7U	Discontinued in Phase 2	ABT-089 affects the binding of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[13]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Selenium	DM25CGV	Approved	Selenium increases the expression of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[10]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4).	[15]

References

• [1] Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q 13.2. Nat Genet. 1995 May;10(1):117-8. doi: 10.1038/ng0595-117.
• [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] A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 1995 Oct;11(2):201-3. doi: 10.1038/ng1095-201.
• [4] 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.
• [5] The C terminus of the human nicotinic alpha4beta2 receptor forms a binding site required for potentiation by an estrogenic steroid. J Neurosci. 2001 Sep 1;21(17):6561-8. doi: 10.1523/JNEUROSCI.21-17-06561.2001.
• [6] 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.
• [7] Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy. Br J Pharmacol. 2002 Jul;136(6):883-95. doi: 10.1038/sj.bjp.0704786.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] 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.
• [10] Rosiglitazone inhibits alpha4 nicotinic acetylcholine receptor expression in human lung carcinoma cells through peroxisome proliferator-activated receptor gamma-independent signals. Mol Cancer Ther. 2009 Jan;8(1):110-8. doi: 10.1158/1535-7163.MCT-08-0719.
• [11] Cholinergic drugs potentiate human nicotinic alpha4beta2 acetylcholine receptors by a competitive mechanism. Eur J Pharmacol. 2005 Feb 21;509(2-3):97-108. doi: 10.1016/j.ejphar.2004.12.037.
• [12] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [13] ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine]: I. A potent and selective cholinergic channel modulator with neuroprotective properties. J Pharmacol Exp Ther. 1997 Oct;283(1):235-46.
• [14] 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.
• [15] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.