Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI7X39E)

• DOT Name: Adenosine receptor A1 (ADORA1)
• Gene Name: ADORA1
• UniProt ID: AA1R_HUMAN
• PDB ID: 5N2S; 5UEN; 6D9H; 7LD3; 7LD4
• Pfam ID: PF00001
• Sequence:
  MPPSISAFQAAYIGIEVLIALVSVPGNVLVIWAVKVNQALRDATFCFIVSLAVADVAVGA
  LVIPLAILINIGPQTYFHTCLMVACPVLILTQSSILALLAIAVDRYLRVKIPLRYKMVVT
  PRRAAVAIAGCWILSFVVGLTPMFGWNNLSAVERAWAANGSMGEPVIKCEFEKVISMEYM
  VYFNFFVWVLPPLLLMVLIYLEVFYLIRKQLNKKVSASSGDPQKYYGKELKIAKSLALIL
  FLFALSWLPLHILNCITLFCPSCHKPSILTYIAIFLTHGNSAMNPIVYAFRIQKFRVTFL
  KIWNDHFRCQPAPPIDEDLPEERPDD
• Function: Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Sphingolipid sig.ling pathway (hsa04071)
  Neuroactive ligand-receptor interaction (hsa04080)
  Regulation of lipolysis in adipocytes (hsa04923)
  Renin secretion (hsa04924)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Adenosine P1 receptors (R-HSA-417973)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Adenosine receptor A1 (ADORA1) affects the response to substance of Aspirin.	[19]
Baclofen	DM0QV1J	Approved	Adenosine receptor A1 (ADORA1) increases the Drug ineffective ADR of Baclofen.	[20]
Formaldehyde	DM7Q6M0	Investigative	Adenosine receptor A1 (ADORA1) increases the Drug dependence ADR of Formaldehyde.	[20]

2 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 Adenosine receptor A1 (ADORA1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Adenosine receptor A1 (ADORA1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Adenosine receptor A1 (ADORA1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adenosine receptor A1 (ADORA1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Adenosine receptor A1 (ADORA1).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Adenosine receptor A1 (ADORA1).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Adenosine receptor A1 (ADORA1).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Adenosine receptor A1 (ADORA1).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Adenosine receptor A1 (ADORA1).	[7]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Adenosine receptor A1 (ADORA1).	[8]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Adenosine receptor A1 (ADORA1).	[9]
Gefitinib	DM15F0X	Approved	Gefitinib decreases the expression of Adenosine receptor A1 (ADORA1).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Adenosine receptor A1 (ADORA1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Adenosine receptor A1 (ADORA1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the activity of Adenosine receptor A1 (ADORA1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Adenosine receptor A1 (ADORA1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Adenosine receptor A1 (ADORA1).	[17]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Adenosine receptor A1 (ADORA1).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine	DMM2NSK	Approved	Adenosine affects the binding of Adenosine receptor A1 (ADORA1).	[11]
GNF-PF-2224	DM26UKN	Investigative	GNF-PF-2224 affects the binding of Adenosine receptor A1 (ADORA1).	[18]

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] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [3] 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.
• [4] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [5] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [9] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [10] Identification of genes linked to gefitinib treatment in prostate cancer cell lines with or without resistance to androgen: a clue to application of gefitinib to hormone-resistant prostate cancer. Oncol Rep. 2006 Jun;15(6):1453-60.
• [11] New 2,6,9-trisubstituted adenines as adenosine receptor antagonists: a preliminary SAR profile. Purinergic Signal. 2007 Sep;3(4):339-46. doi: 10.1007/s11302-007-9068-9. Epub 2007 Sep 19.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [14] 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.
• [15] Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95.
• [16] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [17] 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.
• [18] Pyrimidine derivatives as potent and selective A3 adenosine receptor antagonists. J Med Chem. 2011 Jan 27;54(2):457-71. doi: 10.1021/jm100843z. Epub 2010 Dec 27.
• [19] Adenosine deaminase and adenosine receptor polymorphisms in aspirin-intolerant asthma. Respir Med. 2009 Mar;103(3):356-63. doi: 10.1016/j.rmed.2008.10.008. Epub 2008 Nov 18.
• [20] 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.