Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF0F0FF)

• DOT Name: Muscarinic acetylcholine receptor M4 (CHRM4)
• Gene Name: CHRM4
• UniProt ID: ACM4_HUMAN
• PDB ID: 5DSG; 6D9H; 6KP6; 7LD3; 7LD4; 7TRK; 7TRP; 7TRQ; 7TRS; 7V68; 7V69; 7V6A; 8E9X; 8FX5
• Pfam ID: PF00001
• Sequence:
  MANFTPVNGSSGNQSVRLVTSSSHNRYETVEMVFIATVTGSLSLVTVVGNILVMLSIKVN
  RQLQTVNNYFLFSLACADLIIGAFSMNLYTVYIIKGYWPLGAVVCDLWLALDYVVSNASV
  MNLLIISFDRYFCVTKPLTYPARRTTKMAGLMIAAAWVLSFVLWAPAILFWQFVVGKRTV
  PDNQCFIQFLSNPAVTFGTAIAAFYLPVVIMTVLYIHISLASRSRVHKHRPEGPKEKKAK
  TLAFLKSPLMKQSVKKPPPGEAAREELRNGKLEEAPPPALPPPPRPVADKDTSNESSSGS
  ATQNTKERPATELSTTEATTPAMPAPPLQPRALNPASRWSKIQIVTKQTGNECVTAIEIV
  PATPAGMRPAANVARKFASIARNQVRKKRQMAARERKVTRTIFAILLAFILTWTPYNVMV
  LVNTFCQSCIPDTVWSIGYWLCYVNSTINPACYALCNATFKKTFRHLLLCQYRNIGTAR
• 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 inhibition of adenylate cyclase.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Cholinergic sy.pse (hsa04725)
  Regulation of actin cytoskeleton (hsa04810)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Muscarinic acetylcholine receptors (R-HSA-390648)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbachol	DMX9K8F	Approved	Muscarinic acetylcholine receptor M4 (CHRM4) affects the binding of Carbachol.	[11]
Methylscopolamine	DM5VWOB	Approved	Muscarinic acetylcholine receptor M4 (CHRM4) affects the binding of Methylscopolamine.	[11]
[3H]oxotremorine-M	DM5L7D3	Investigative	Muscarinic acetylcholine receptor M4 (CHRM4) affects the binding of [3H]oxotremorine-M.	[11]
furtrethonium	DM4M3C8	Investigative	Muscarinic acetylcholine receptor M4 (CHRM4) affects the binding of furtrethonium.	[11]
methylfurmethide	DMZ318I	Investigative	Muscarinic acetylcholine receptor M4 (CHRM4) affects the binding of methylfurmethide.	[11]

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 Muscarinic acetylcholine receptor M4 (CHRM4).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Muscarinic acetylcholine receptor M4 (CHRM4).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Muscarinic acetylcholine receptor M4 (CHRM4).	[2]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Muscarinic acetylcholine receptor M4 (CHRM4).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Muscarinic acetylcholine receptor M4 (CHRM4).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Muscarinic acetylcholine receptor M4 (CHRM4).	[8]

7 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 M4 (CHRM4).	[4]
Atropine	DMEN6X7	Approved	Atropine affects the binding of Muscarinic acetylcholine receptor M4 (CHRM4).	[5]
ALCURONIUM	DM2U4XQ	Approved	ALCURONIUM affects the binding of Muscarinic acetylcholine receptor M4 (CHRM4).	[5]
brucine	DM50RUD	Investigative	brucine affects the binding of Muscarinic acetylcholine receptor M4 (CHRM4).	[5]
	DM1FBZ7		affects the binding of Muscarinic acetylcholine receptor M4 (CHRM4).	[9]
[3H]QNB	DMC1WHR	Investigative	[3H]QNB affects the binding of Muscarinic acetylcholine receptor M4 (CHRM4).	[10]
McN-A-343	DML3AZG	Investigative	McN-A-343 affects the binding of Muscarinic acetylcholine receptor M4 (CHRM4).	[5]

References

• [1] 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.
• [2] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [3] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [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] Interaction studies of multiple binding sites on m4 muscarinic acetylcholine receptors. Mol Pharmacol. 2006 Aug;70(2):736-46. doi: 10.1124/mol.106.024711. Epub 2006 May 18.
• [6] 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.
• [7] 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.
• [8] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [9] 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.
• [10] 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.
• [11] Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mol Pharmacol. 1997 Jul;52(1):172-9.