Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKSD095)

• DOT Name: Muscarinic acetylcholine receptor M3 (CHRM3)
• Gene Name: CHRM3
• Related Disease: Prune belly syndrome
• UniProt ID: ACM3_HUMAN
• PDB ID: 2CSA; 8E9W; 8E9Y; 8E9Z; 8EA0
• Pfam ID: PF00001
• Sequence:
  MTLHNNSTTSPLFPNISSSWIHSPSDAGLPPGTVTHFGSYNVSRAAGNFSSPDGTTDDPL
  GGHTVWQVVFIAFLTGILALVTIIGNILVIVSFKVNKQLKTVNNYFLLSLACADLIIGVI
  SMNLFTTYIIMNRWALGNLACDLWLAIDYVASNASVMNLLVISFDRYFSITRPLTYRAKR
  TTKRAGVMIGLAWVISFVLWAPAILFWQYFVGKRTVPPGECFIQFLSEPTITFGTAIAAF
  YMPVTIMTILYWRIYKETEKRTKELAGLQASGTEAETENFVHPTGSSRSCSSYELQQQSM
  KRSNRRKYGRCHFWFTTKSWKPSSEQMDQDHSSSDSWNNNDAAASLENSASSDEEDIGSE
  TRAIYSIVLKLPGHSTILNSTKLPSSDNLQVPEEELGMVDLERKADKLQAQKSVDDGGSF
  PKSFSKLPIQLESAVDTAKTSDVNSSVGKSTATLPLSFKEATLAKRFALKTRSQITKRKR
  MSLVKEKKAAQTLSAILLAFIITWTPYNIMVLVNTFCDSCIPKTFWNLGYWLCYINSTVN
  PVCYALCNKTFRTTFKMLLLCQCDKKKRRKQQYQQRQSVIFHKRAPEQAL
• Function: The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
  Cholinergic sy.pse (hsa04725)
  Taste transduction (hsa04742)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin secretion (hsa04911)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  Acetylcholine regulates insulin secretion (R-HSA-399997)
  G alpha (q) signalling events (R-HSA-416476)
  Muscarinic acetylcholine receptors (R-HSA-390648)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prune belly syndrome	DISBIBMN	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 7 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Muscarinic acetylcholine receptor M3 (CHRM3) increases the Metabolic disorder ADR of Chlorothiazide.	[17]
Methylscopolamine	DM5VWOB	Approved	Muscarinic acetylcholine receptor M3 (CHRM3) affects the binding of Methylscopolamine.	[18]
Arecoline	DMFJZK3	Phase 1	Muscarinic acetylcholine receptor M3 (CHRM3) affects the binding of Arecoline.	[18]
[3H]oxotremorine-M	DM5L7D3	Investigative	Muscarinic acetylcholine receptor M3 (CHRM3) affects the binding of [3H]oxotremorine-M.	[18]
furtrethonium	DM4M3C8	Investigative	Muscarinic acetylcholine receptor M3 (CHRM3) affects the binding of furtrethonium.	[18]
methylfurmethide	DMZ318I	Investigative	Muscarinic acetylcholine receptor M3 (CHRM3) affects the binding of methylfurmethide.	[18]
McN-A-343	DML3AZG	Investigative	Muscarinic acetylcholine receptor M3 (CHRM3) affects the binding of McN-A-343.	[18]

15 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 Muscarinic acetylcholine receptor M3 (CHRM3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Muscarinic acetylcholine receptor M3 (CHRM3).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Muscarinic acetylcholine receptor M3 (CHRM3).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Muscarinic acetylcholine receptor M3 (CHRM3).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Muscarinic acetylcholine receptor M3 (CHRM3).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Muscarinic acetylcholine receptor M3 (CHRM3).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Muscarinic acetylcholine receptor M3 (CHRM3).	[7]
Carbachol	DMX9K8F	Approved	Carbachol increases the activity of Muscarinic acetylcholine receptor M3 (CHRM3).	[8]
Acetylcholine	DMDF79Z	Approved	Acetylcholine increases the activity of Muscarinic acetylcholine receptor M3 (CHRM3).	[9]
Atropine	DMEN6X7	Approved	Atropine decreases the activity of Muscarinic acetylcholine receptor M3 (CHRM3).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Muscarinic acetylcholine receptor M3 (CHRM3).	[7]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Muscarinic acetylcholine receptor M3 (CHRM3).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Muscarinic acetylcholine receptor M3 (CHRM3).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Muscarinic acetylcholine receptor M3 (CHRM3).	[12]
Paraoxon	DMN4ZKC	Investigative	Paraoxon decreases the expression of Muscarinic acetylcholine receptor M3 (CHRM3).	[13]

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 Muscarinic acetylcholine receptor M3 (CHRM3).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Muscarinic acetylcholine receptor M3 (CHRM3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
brucine	DM50RUD	Investigative	brucine affects the binding of Muscarinic acetylcholine receptor M3 (CHRM3).	[14]
	DM1FBZ7		affects the binding of Muscarinic acetylcholine receptor M3 (CHRM3).	[15]
[3H]QNB	DMC1WHR	Investigative	[3H]QNB affects the binding of Muscarinic acetylcholine receptor M3 (CHRM3).	[16]
[3H]strychnine	DM0Y2SC	Investigative	[3H]strychnine affects the binding of Muscarinic acetylcholine receptor M3 (CHRM3).	[14]

References

• [1] Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9579-84. doi: 10.1073/pnas.97.17.9579.
• [2] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] Zinc oxide nanoparticle disruption of store-operated calcium entry in a muscarinic receptor signaling pathway. Toxicol In Vitro. 2010 Oct;24(7):1953-61. doi: 10.1016/j.tiv.2010.08.005. Epub 2010 Aug 12.
• [9] Assessment of false transmitters as treatments for nerve agent poisoning. Toxicol Lett. 2020 Mar 15;321:21-31. doi: 10.1016/j.toxlet.2019.12.010. Epub 2019 Dec 9.
• [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] 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.
• [12] 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.
• [13] Effects of paraoxon on neuronal and lymphocytic cholinergic systems. Environ Toxicol Pharmacol. 2011 Jan;31(1):119-28.
• [14] Asparagine, valine, and threonine in the third extracellular loop of muscarinic receptor have essential roles in the positive cooperativity of strychnine-like allosteric modulators. J Pharmacol Exp Ther. 2005 May;313(2):688-96. doi: 10.1124/jpet.104.080358. Epub 2005 Jan 12.
• [15] Inhalation by design: novel tertiary amine muscarinic M? receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease. J Med Chem. 2011 Oct 13;54(19):6888-904. doi: 10.1021/jm200884j. Epub 2011 Sep 20.
• [16] A snake venom inhibitor to muscarinic acetylcholine receptor (mAChR): isolation and interaction with cloned human mAChR. Arch Biochem Biophys. 2000 May 15;377(2):290-5. doi: 10.1006/abbi.2000.1784.
• [17] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.
• [18] Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mol Pharmacol. 1997 Jul;52(1):172-9.