Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO23NRK)

• DOT Name: G-protein coupled receptor 35 (GPR35)
• Synonyms: Kynurenic acid receptor; KYNA receptor
• Gene Name: GPR35
• UniProt ID: GPR35_HUMAN
• PDB ID: 8H8J
• Pfam ID: PF00001
• Sequence:
  MNGTYNTCGSSDLTWPPAIKLGFYAYLGVLLVLGLLLNSLALWVFCCRMQQWTETRIYMT
  NLAVADLCLLCTLPFVLHSLRDTSDTPLCQLSQGIYLTNRYMSISLVTAIAVDRYVAVRH
  PLRARGLRSPRQAAAVCAVLWVLVIGSLVARWLLGIQEGGFCFRSTRHNFNSMAFPLLGF
  YLPLAVVVFCSLKVVTALAQRPPTDVGQAEATRKAARMVWANLLVFVVCFLPLHVGLTVR
  LAVGWNACALLETIRRALYITSKLSDANCCLDAICYYYMAKEFQEASALAVAPSAKAHKS
  QDSLCVTLA
• Function: G-protein coupled receptor that binds to several ligands including the tryptophan metabolite kynurenic acid (KYNA), lysophosphatidic acid (LPA) or 5-hydroxyindoleacetic acid (5-HIAA) with high affinity, leading to rapid and transient activation of numerous intracellular signaling pathways. Plays a role in neutrophil recruitment to sites of inflammation and bacterial clearance through the major serotonin metabolite 5-HIAA that acts as a physiological ligand. Stimulates lipid metabolism, thermogenic, and anti-inflammatory gene expression in adipose tissue once activated by kynurenic acid. In macrophages, activation by lysophosphatidic acid promotes GPR35-induced signaling with a distinct transcriptional profile characterized by TNF production associated with ERK and NF-kappa-B activation. In turn, induces chemotaxis of macrophages.
• Tissue Specificity: Predominantly expressed in immune and gastrointestinal tissues.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway: Class A/1 (Rhodopsin-like receptors) (R-HSA-373076)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	G-protein coupled receptor 35 (GPR35) decreases the response to substance of Paclitaxel.	[10]

3 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 G-protein coupled receptor 35 (GPR35).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of G-protein coupled receptor 35 (GPR35).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of G-protein coupled receptor 35 (GPR35).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of G-protein coupled receptor 35 (GPR35).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of G-protein coupled receptor 35 (GPR35).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of G-protein coupled receptor 35 (GPR35).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of G-protein coupled receptor 35 (GPR35).	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of G-protein coupled receptor 35 (GPR35).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Zaprinast	DMGH3T5	Terminated	Zaprinast affects the localization of G-protein coupled receptor 35 (GPR35).	[9]
pamoic acid	DM7M5AF	Investigative	pamoic acid affects the localization of G-protein coupled receptor 35 (GPR35).	[9]

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] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] 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.
• [7] Identification of novel genes associated with the response to 5-FU treatment in gastric cancer cell lines using a cDNA microarray. Cancer Lett. 2004 Oct 8;214(1):19-33.
• [8] 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.
• [9] Antagonists of GPR35 display high species ortholog selectivity and varying modes of action. J Pharmacol Exp Ther. 2012 Dec;343(3):683-95. doi: 10.1124/jpet.112.198945. Epub 2012 Sep 11.
• [10] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.