Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTJXD24)

• DOT Name: Acetylcholine receptor subunit beta (CHRNB1)
• Gene Name: CHRNB1
• Related Disease:
  Congenital myasthenic syndrome 2A
  Congenital myasthenic syndrome 2C
  Congenital myasthenic syndrome 1A
  Alcohol dependence
  Postsynaptic congenital myasthenic syndrome
• UniProt ID: ACHB_HUMAN
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MTPGALLMLLGALGAPLAPGVRGSEAEGRLREKLFSGYDSSVRPAREVGDRVRVSVGLIL
  AQLISLNEKDEEMSTKVYLDLEWTDYRLSWDPAEHDGIDSLRITAESVWLPDVVLLNNND
  GNFDVALDISVVVSSDGSVRWQPPGIYRSSCSIQVTYFPFDWQNCTMVFSSYSYDSSEVS
  LQTGLGPDGQGHQEIHIHEGTFIENGQWEIIHKPSRLIQPPGDPRGGREGQRQEVIFYLI
  IRRKPLFYLVNVIAPCILITLLAIFVFYLPPDAGEKMGLSIFALLTLTVFLLLLADKVPE
  TSLSVPIIIKYLMFTMVLVTFSVILSVVVLNLHHRSPHTHQMPLWVRQIFIHKLPLYLRL
  KRPKPERDLMPEPPHCSSPGSGWGRGTDEYFIRKPPSDFLFPKPNRFQPELSAPDLRRFI
  DGPNRAVALLPELREVVSSISYIARQLQEQEDHDALKEDWQFVAMVVDRLFLWTFIIFTS
  VGTLVIFLDATYHLPPPDPFP
• 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.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myasthenic syndrome 2A	DIS5KYRE	Definitive	Autosomal dominant	[1]
Congenital myasthenic syndrome 2C	DIST46DD	Definitive	Autosomal recessive	[2]
Congenital myasthenic syndrome 1A	DIS4PQM3	Strong	Autosomal dominant	[3]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[4]
Postsynaptic congenital myasthenic syndrome	DIS92VN2	Supportive	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Acetylcholine receptor subunit beta (CHRNB1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Acetylcholine receptor subunit beta (CHRNB1).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Acetylcholine receptor subunit beta (CHRNB1).	[8]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Acetylcholine receptor subunit beta (CHRNB1).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Acetylcholine receptor subunit beta (CHRNB1).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Acetylcholine receptor subunit beta (CHRNB1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Acetylcholine receptor subunit beta (CHRNB1).	[13]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Acetylcholine receptor subunit beta (CHRNB1).	[15]

2 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 decreases the methylation of Acetylcholine receptor subunit beta (CHRNB1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Acetylcholine receptor subunit beta (CHRNB1).	[14]

References

• [1] Mutations Causing Slow-Channel Myasthenia Reveal That a Valine Ring in the Channel Pore of Muscle AChR is Optimized for Stabilizing Channel Gating. Hum Mutat. 2016 Oct;37(10):1051-9. doi: 10.1002/humu.23043. Epub 2016 Aug 21.
• [2] CHRNB1-associated congenital myasthenia syndrome: Expanding the clinical spectrum. Am J Med Genet A. 2021 Mar;185(3):827-835. doi: 10.1002/ajmg.a.62011. Epub 2020 Dec 9.
• [3] New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum Mol Genet. 1996 Sep;5(9):1217-27. doi: 10.1093/hmg/5.9.1217.
• [4] Associations of rare nicotinic cholinergic receptor gene variants to nicotine and alcohol dependence.Am J Med Genet B Neuropsychiatr Genet. 2016 Dec;171(8):1057-1071. doi: 10.1002/ajmg.b.32476. Epub 2016 Jul 30.
• [5] Congenital Myasthenic Syndromes Overview. 2003 May 9 [updated 2021 Dec 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [9] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [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] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] 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.
• [15] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.