Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVRBZ0I)

• DOT Name: Adenosine receptor A2a (ADORA2A)
• Gene Name: ADORA2A
• UniProt ID: AA2AR_HUMAN
• PDB ID: 2YDO ; 2YDV ; 3EML ; 3PWH ; 3QAK ; 3REY ; 3RFM ; 3UZA ; 3UZC ; 3VG9 ; 3VGA ; 4EIY ; 4UG2 ; 4UHR ; 5G53 ; 5IU4 ; 5IU7 ; 5IU8 ; 5IUA ; 5IUB ; 5JTB ; 5K2A ; 5K2B ; 5K2C ; 5K2D ; 5MZJ ; 5MZP ; 5N2R ; 5NLX ; 5NM2 ; 5NM4 ; 5OLG ; 5OLH ; 5OLO ; 5OLV ; 5OLZ ; 5OM1 ; 5OM4 ; 5UIG ; 5UVI ; 5VRA ; 5WF5 ; 5WF6 ; 6AQF ; 6GDG ; 6GT3 ; 6JZH ; 6LPJ ; 6LPK ; 6LPL ; 6MH8 ; 6PS7 ; 6S0L ; 6S0Q ; 6WQA ; 6ZDR ; 6ZDV ; 7ARO ; 7EZC ; 7PX4 ; 7PYR ; 7RM5 ; 7T32 ; 8A2O ; 8A2P ; 8C9W ; 8CIC ; 8CU6 ; 8CU7 ; 8DU3 ; 8GNE ; 8GNG ; 8JWY ; 8JWZ ; 8PWN
• Pfam ID: PF00001
• Sequence:
  MPIMGSSVYITVELAIAVLAILGNVLVCWAVWLNSNLQNVTNYFVVSLAAADIAVGVLAI
  PFAITISTGFCAACHGCLFIACFVLVLTQSSIFSLLAIAIDRYIAIRIPLRYNGLVTGTR
  AKGIIAICWVLSFAIGLTPMLGWNNCGQPKEGKNHSQGCGEGQVACLFEDVVPMNYMVYF
  NFFACVLVPLLLMLGVYLRIFLAARRQLKQMESQPLPGERARSTLQKEVHAAKSLAIIVG
  LFALCWLPLHIINCFTFFCPDCSHAPLWLMYLAIVLSHTNSVVNPFIYAYRIREFRQTFR
  KIIRSHVLRQQEPFKAAGTSARVLAAHGSDGEQVSLRLNGHPPGVWANGSAPHPERRPNG
  YALGLVSGGSAQESQGNTGLPDVELLSHELKGVCPEPPGLDDPLAQDGAGVS
• Function: Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Vascular smooth muscle contraction (hsa04270)
  Parkinson disease (hsa05012)
  Alcoholism (hsa05034)
• Reactome Pathway:
  Adenosine P1 receptors (R-HSA-417973)
  G alpha (s) signalling events (R-HSA-418555)
  Surfactant metabolism (R-HSA-5683826)
  NGF-independant TRKA activation (R-HSA-187024)

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 A2a (ADORA2A) affects the response to substance of Aspirin.	[20]
Methamphetamine	DMPM4SK	Approved	Adenosine receptor A2a (ADORA2A) increases the response to substance of Methamphetamine.	[21]
Amphetamine	DMSZQAK	Approved	Adenosine receptor A2a (ADORA2A) increases the response to substance of Amphetamine.	[22]

17 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 Adenosine receptor A2a (ADORA2A).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Adenosine receptor A2a (ADORA2A).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Adenosine receptor A2a (ADORA2A).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Adenosine receptor A2a (ADORA2A).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Adenosine receptor A2a (ADORA2A).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Adenosine receptor A2a (ADORA2A).	[6]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Adenosine receptor A2a (ADORA2A).	[7]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Adenosine receptor A2a (ADORA2A).	[7]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Adenosine receptor A2a (ADORA2A).	[8]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Adenosine receptor A2a (ADORA2A).	[7]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Adenosine receptor A2a (ADORA2A).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Adenosine receptor A2a (ADORA2A).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide affects the expression of Adenosine receptor A2a (ADORA2A).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Adenosine receptor A2a (ADORA2A).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Adenosine receptor A2a (ADORA2A).	[14]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Adenosine receptor A2a (ADORA2A).	[16]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of Adenosine receptor A2a (ADORA2A).	[18]

3 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 A2a (ADORA2A).	[9]
ZM-241385	DMWQ38G	Terminated	ZM-241385 affects the binding of Adenosine receptor A2a (ADORA2A).	[15]
GNF-PF-2224	DM26UKN	Investigative	GNF-PF-2224 affects the binding of Adenosine receptor A2a (ADORA2A).	[19]

2 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 affects the methylation of Adenosine receptor A2a (ADORA2A).	[11]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the acetylation of Adenosine receptor A2a (ADORA2A).	[17]

References

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• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Adenosine receptor expression in rheumatoid synovium: a basis for methotrexate action. Arthritis Res Ther. 2012 Jun 8;14(3):R138. doi: 10.1186/ar3871.
• [7] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [8] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] Prenatal caffeine exposure induced a lower level of fetal blood leptin mainly via placental mechanism. Toxicol Appl Pharmacol. 2015 Nov 15;289(1):109-16. doi: 10.1016/j.taap.2015.09.007. Epub 2015 Sep 12.
• [15] 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.
• [16] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [17] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [18] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.
• [19] Discovery of phosphoric acid mono-{2-[(E/Z)-4-(3,3-dimethyl-butyrylamino)-3,5-difluoro-benzoylimino]-thiazol-3-ylmethyl} ester (Lu AA47070): a phosphonooxymethylene prodrug of a potent and selective hA(2A) receptor antagonist. J Med Chem. 2011 Feb 10;54(3):751-64. doi: 10.1021/jm1008659. Epub 2011 Jan 6.
• [20] 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.
• [21] The adenosine A2A receptor is associated with methamphetamine dependence/psychosis in the Japanese population. Behav Brain Funct. 2010 Aug 30;6:50. doi: 10.1186/1744-9081-6-50.
• [22] Interindividual variation in anxiety response to amphetamine: possible role for adenosine A2A receptor gene variants. Am J Med Genet B Neuropsychiatr Genet. 2005 Nov 5;139B(1):42-4. doi: 10.1002/ajmg.b.30228.