Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNAT2M5)

• DOT Name: Neuronal acetylcholine receptor subunit beta-2 (CHRNB2)
• Gene Name: CHRNB2
• Related Disease:
  Sleep-related hypermotor epilepsy
  Autosomal dominant nocturnal frontal lobe epilepsy 3
  Autosomal dominant nocturnal frontal lobe epilepsy
• UniProt ID: ACHB2_HUMAN
• PDB ID: 2K58; 2K59; 2KSR; 2LM2; 5KXI; 6CNJ; 6CNK; 6UR8; 6USF
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MARRCGPVALLLGFGLLRLCSGVWGTDTEERLVEHLLDPSRYNKLIRPATNGSELVTVQL
  MVSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLY
  NNADGMYEVSFYSNAVVSYDGSIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDR
  TEIDLVLKSEVASLDDFTPSGEWDIVALPGRRNENPDDSTYVDITYDFIIRRKPLFYTIN
  LIIPCVLITSLAILVFYLPSDCGEKMTLCISVLLALTVFLLLISKIVPPTSLDVPLVGKY
  LMFTMVLVTFSIVTSVCVLNVHHRSPTTHTMAPWVKVVFLEKLPALLFMQQPRHHCARQR
  LRLRRRQREREGAGALFFREAPGADSCTCFVNRASVQGLAGAFGAEPAPVAGPGRSGEPC
  GCGLREAVDGVRFIADHMRSEDDDQSVSEDWKYVAMVIDRLFLWIFVFVCVFGTIGMFLQ
  PLFQNYTTTTFLHSDHSAPSSK
• 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 sodiun 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
Sleep-related hypermotor epilepsy	DISWP477	Definitive	Autosomal dominant	[1]
Autosomal dominant nocturnal frontal lobe epilepsy 3	DISRI6CO	Strong	Autosomal dominant	[2]
Autosomal dominant nocturnal frontal lobe epilepsy	DISE3C4O	Supportive	Autosomal dominant	[2]

2 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 beta-2 (CHRNB2).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[5]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[7]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the binding of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[6]
Atropine	DMEN6X7	Approved	Atropine affects the binding of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[8]
Rivastigmine	DMG629M	Approved	Rivastigmine affects the binding of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[8]
Scopolamine	DMOM8AL	Approved	Scopolamine affects the binding of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[8]
Galantamine	DMEO794	Approved	Galantamine affects the binding of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[8]
CYTISINE	DMUF0BJ	Phase 3	CYTISINE affects the binding of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[9]
Physostigmine	DM2N0TO	Discontinued in Phase 2	Physostigmine affects the binding of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[8]
ABT-089	DM8DT7U	Discontinued in Phase 2	ABT-089 affects the binding of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[9]
Epibatidine	DMAGZD8	Investigative	Epibatidine affects the binding of Neuronal acetylcholine receptor subunit beta-2 (CHRNB2).	[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] The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet. 2000 Nov;26(3):275-6. doi: 10.1038/81566.
• [3] 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.
• [4] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [5] 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.
• [6] 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.
• [7] Repetitive nicotine exposure leads to a more malignant and metastasis-prone phenotype of SCLC: a molecular insight into the importance of quitting smoking during treatment. Toxicol Sci. 2010 Aug;116(2):467-76. doi: 10.1093/toxsci/kfq138. Epub 2010 May 10.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Characterization of human alpha 4 beta 2-nicotinic acetylcholine receptors stably and heterologously expressed in native nicotinic receptor-null SH-EP1 human epithelial cells. Mol Pharmacol. 2003 Dec;64(6):1283-94. doi: 10.1124/mol.64.6.1283.