Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6VFHX9)

• DOT Name: Melatonin receptor type 1B (MTNR1B)
• Synonyms: Mel-1B-R; Mel1b receptor
• Gene Name: MTNR1B
• UniProt ID: MTR1B_HUMAN
• PDB ID: 6ME6; 6ME7; 6ME8; 6ME9; 7VH0
• Pfam ID: PF00001
• Sequence:
  MSENGSFANCCEAGGWAVRPGWSGAGSARPSRTPRPPWVAPALSAVLIVTTAVDVVGNLL
  VILSVLRNRKLRNAGNLFLVSLALADLVVAFYPYPLILVAIFYDGWALGEEHCKASAFVM
  GLSVIGSVFNITAIAINRYCYICHSMAYHRIYRRWHTPLHICLIWLLTVVALLPNFFVGS
  LEYDPRIYSCTFIQTASTQYTAAVVVIHFLLPIAVVSFCYLRIWVLVLQARRKAKPESRL
  CLKPSDLRSFLTMFVVFVIFAICWAPLNCIGLAVAINPQEMAPQIPEGLFVTSYLLAYFN
  SCLNAIVYGLLNQNFRREYKRILLALWNPRHCIQDASKGSHAEGLQSPAPPIIGVQHQAD
  AL
• Function: High affinity receptor for melatonin. Likely to mediate the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity.
• Tissue Specificity: Expressed in retina and less in brain and hippocampus.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Circadian entrainment (hsa04713)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Class A/1 (Rhodopsin-like receptors) (R-HSA-373076)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Melatonin receptor type 1B (MTNR1B) affects the abundance of Testosterone.	[9]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Melatonin receptor type 1B (MTNR1B).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Melatonin receptor type 1B (MTNR1B).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Melatonin receptor type 1B (MTNR1B).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Melatonin receptor type 1B (MTNR1B).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Melatonin	DMKWFBT	Approved	Melatonin affects the binding of Melatonin receptor type 1B (MTNR1B).	[4]
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the binding of Melatonin receptor type 1B (MTNR1B).	[5]
Agomelatine	DMXYA5K	Withdrawn from market	Agomelatine affects the binding of Melatonin receptor type 1B (MTNR1B).	[7]
CHRYSOERIOL	DM96ECL	Investigative	CHRYSOERIOL affects the binding of Melatonin receptor type 1B (MTNR1B).	[5]
4P-PDOT	DMEMN0W	Investigative	4P-PDOT affects the binding of Melatonin receptor type 1B (MTNR1B).	[8]

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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [4] Melatonin antagonizes apoptosis via receptor interaction in U937 monocytic cells. J Pineal Res. 2007 Sep;43(2):154-62. doi: 10.1111/j.1600-079X.2007.00455.x.
• [5] Old and new inhibitors of quinone reductase 2. Chem Biol Interact. 2010 Jul 30;186(2):103-9. doi: 10.1016/j.cbi.2010.04.006. Epub 2010 May 4.
• [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] Synthesis of phenalene and acenaphthene derivatives as new conformationally restricted ligands for melatonin receptors. J Med Chem. 2000 Nov 2;43(22):4051-62. doi: 10.1021/jm000922c.
• [8] Toward the definition of stereochemical requirements for MT2-selective antagonists and partial agonists by studying 4-phenyl-2-propionamidotetralin derivatives. J Med Chem. 2011 Dec 22;54(24):8362-72. doi: 10.1021/jm200790v. Epub 2011 Nov 18.
• [9] Common genetic variation in MTNR1B is associated with serum testosterone, glucose tolerance, and insulin secretion in polycystic ovary syndrome patients. Fertil Steril. 2010 Nov;94(6):2486-9, 2489.e1-2. doi: 10.1016/j.fertnstert.2010.01.059. Epub 2010 Mar 6.