Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUMZ2WR)

• DOT Name: Muscarinic acetylcholine receptor M2 (CHRM2)
• Gene Name: CHRM2
• UniProt ID: ACM2_HUMAN
• PDB ID: 3UON; 4MQS; 4MQT; 5YC8; 5ZK3; 5ZK8; 5ZKB; 5ZKC; 6OIK; 6U1N; 7T8X; 7T90; 7T94; 7T96
• Pfam ID: PF00001
• Sequence:
  MNNSTNSSNNSLALTSPYKTFEVVFIVLVAGSLSLVTIIGNILVMVSIKVNRHLQTVNNY
  FLFSLACADLIIGVFSMNLYTLYTVIGYWPLGPVVCDLWLALDYVVSNASVMNLLIISFD
  RYFCVTKPLTYPVKRTTKMAGMMIAAAWVLSFILWAPAILFWQFIVGVRTVEDGECYIQF
  FSNAAVTFGTAIAAFYLPVIIMTVLYWHISRASKSRIKKDKKEPVANQDPVSPSLVQGRI
  VKPNNNNMPSSDDGLEHNKIQNGKAPRDPVTENCVQGEEKESSNDSTSVSAVASNMRDDE
  ITQDENTVSTSLGHSKDENSKQTCIRIGTKTPKSDSCTPTNTTVEVVGSSGQNGDEKQNI
  VARKIVKMTKQPAKKKPPPSREKKVTRTILAILLAFIITWAPYNVMVLINTFCAPCIPNT
  VWTIGYWLCYINSTINPACYALCNATFKKTFKHLLMCHYKNIGATR
• 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 adenylate cyclase inhibition. Signaling promotes phospholipase C activity, leading to the release of inositol trisphosphate (IP3); this then triggers calcium ion release into the cytosol.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  PI3K-Akt sig.ling pathway (hsa04151)
  Cholinergic sy.pse (hsa04725)
  Regulation of actin cytoskeleton (hsa04810)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Muscarinic acetylcholine receptors (R-HSA-390648)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 8 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbachol	DMX9K8F	Approved	Muscarinic acetylcholine receptor M2 (CHRM2) affects the binding of Carbachol.	[15]
Methylscopolamine	DM5VWOB	Approved	Muscarinic acetylcholine receptor M2 (CHRM2) affects the binding of Methylscopolamine.	[16]
Gallamine Triethiodide	DMPO0MS	Approved	Muscarinic acetylcholine receptor M2 (CHRM2) affects the binding of Gallamine Triethiodide.	[16]
Sabcomeline	DMCEOAJ	Discontinued in Phase 1	Muscarinic acetylcholine receptor M2 (CHRM2) increases the Bradycardia ADR of Sabcomeline.	[17]
[3H]oxotremorine-M	DM5L7D3	Investigative	Muscarinic acetylcholine receptor M2 (CHRM2) affects the binding of [3H]oxotremorine-M.	[15]
furtrethonium	DM4M3C8	Investigative	Muscarinic acetylcholine receptor M2 (CHRM2) affects the binding of furtrethonium.	[15]
methylfurmethide	DMZ318I	Investigative	Muscarinic acetylcholine receptor M2 (CHRM2) affects the binding of methylfurmethide.	[15]
[3H]dimethyl-W84	DMBWAIE	Investigative	Muscarinic acetylcholine receptor M2 (CHRM2) affects the binding of [3H]dimethyl-W84.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Muscarinic acetylcholine receptor M2 (CHRM2).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Muscarinic acetylcholine receptor M2 (CHRM2).	[2]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Muscarinic acetylcholine receptor M2 (CHRM2).	[3]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the activity of Muscarinic acetylcholine receptor M2 (CHRM2).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Muscarinic acetylcholine receptor M2 (CHRM2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Muscarinic acetylcholine receptor M2 (CHRM2).	[9]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Muscarinic acetylcholine receptor M2 (CHRM2).	[10]
Paraoxon	DMN4ZKC	Investigative	Paraoxon decreases the expression of Muscarinic acetylcholine receptor M2 (CHRM2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetylcholine	DMDF79Z	Approved	Acetylcholine affects the binding of Muscarinic acetylcholine receptor M2 (CHRM2).	[4]
Omadacycline	DMR2J95	Approved	Omadacycline affects the binding of Muscarinic acetylcholine receptor M2 (CHRM2).	[5]
brucine	DM50RUD	Investigative	brucine affects the binding of Muscarinic acetylcholine receptor M2 (CHRM2).	[12]
	DM1FBZ7		affects the binding of Muscarinic acetylcholine receptor M2 (CHRM2).	[13]
[3H]QNB	DMC1WHR	Investigative	[3H]QNB affects the binding of Muscarinic acetylcholine receptor M2 (CHRM2).	[14]
[3H]strychnine	DM0Y2SC	Investigative	[3H]strychnine affects the binding of Muscarinic acetylcholine receptor M2 (CHRM2).	[12]

1 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 Muscarinic acetylcholine receptor M2 (CHRM2).	[7]

References

• [1] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [2] 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.
• [3] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [4] Allosteric effects of four stereoisomers of a fused indole ring system with 3H-N-methylscopolamine and acetylcholine at M1-M4 muscarinic receptors. Life Sci. 1999;64(6-7):519-26. doi: 10.1016/s0024-3205(98)00596-7.
• [5] In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5247-53. doi: 10.1128/AAC.00320-16. Print 2016 Sep.
• [6] Characterization of the potent, selective Nrf2 activator, 3-(pyridin-3-ylsulfonyl)-5-(trifluoromethyl)-2H-chromen-2-one, in cellular and in vivo models of pulmonary oxidative stress. J Pharmacol Exp Ther. 2017 Oct;363(1):114-125.
• [7] 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.
• [8] 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.
• [9] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [10] Postnatal exposure to chlorpyrifos produces long-term effects on spatial memory and the cholinergic system in mice in a sex- and APOE genotype-dependent manner. Food Chem Toxicol. 2018 Dec;122:1-10. doi: 10.1016/j.fct.2018.09.069. Epub 2018 Sep 29.
• [11] Effects of paraoxon on neuronal and lymphocytic cholinergic systems. Environ Toxicol Pharmacol. 2011 Jan;31(1):119-28.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mol Pharmacol. 1997 Jul;52(1):172-9.
• [16] Allosteric interactions with muscarinic acetylcholine receptors: complex role of the conserved tryptophan M2422Trp in a critical cluster of amino acids for baseline affinity, subtype selectivity, and cooperativity. Mol Pharmacol. 2006 Jul;70(1):181-93. doi: 10.1124/mol.106.023481. Epub 2006 Apr 26.
• [17] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.