Details of Drug Off-Target (DOT)

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

• DOT Name: Sphingosine 1-phosphate receptor 1 (S1PR1)
• Synonyms: S1P receptor 1; S1P1; Endothelial differentiation G-protein coupled receptor 1; Sphingosine 1-phosphate receptor Edg-1; S1P receptor Edg-1; CD antigen CD363
• Gene Name: S1PR1
• UniProt ID: S1PR1_HUMAN
• PDB ID: 3V2W; 3V2Y; 7EO2; 7EO4; 7EVY; 7EVZ; 7EW0; 7EW7; 7TD3; 7TD4; 7VIE; 7VIF; 7VIG; 7VIH; 7WF7; 8G94
• Pfam ID: PF00001
• Sequence:
  MGPTSVPLVKAHRSSVSDYVNYDIIVRHYNYTGKLNISADKENSIKLTSVVFILICCFII
  LENIFVLLTIWKTKKFHRPMYYFIGNLALSDLLAGVAYTANLLLSGATTYKLTPAQWFLR
  EGSMFVALSASVFSLLAIAIERYITMLKMKLHNGSNNFRLFLLISACWVISLILGGLPIM
  GWNCISALSSCSTVLPLYHKHYILFCTTVFTLLLLSIVILYCRIYSLVRTRSRRLTFRKN
  ISKASRSSEKSLALLKTVIIVLSVFIACWAPLFILLLLDVGCKVKTCDILFRAEYFLVLA
  VLNSGTNPIIYTLTNKEMRRAFIRIMSCCKCPSGDSAGKFKRPIIAGMEFSRSKSDNSSH
  PQKDEGDNPETIMSSGNVNSSS
• Function: G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activation of RAC1, SRC, PTK2/FAK1 and MAP kinases. Plays an important role in cell migration, probably via its role in the reorganization of the actin cytoskeleton and the formation of lamellipodia in response to stimuli that increase the activity of the sphingosine kinase SPHK1. Required for normal chemotaxis toward sphingosine 1-phosphate. Required for normal embryonic heart development and normal cardiac morphogenesis. Plays an important role in the regulation of sprouting angiogenesis and vascular maturation. Inhibits sprouting angiogenesis to prevent excessive sprouting during blood vessel development. Required for normal egress of mature T-cells from the thymus into the blood stream and into peripheral lymphoid organs. Plays a role in the migration of osteoclast precursor cells, the regulation of bone mineralization and bone homeostasis. Plays a role in responses to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine by pulmonary endothelial cells and in the protection against ventilator-induced lung injury.
• Tissue Specificity: Endothelial cells, and to a lesser extent, in vascular smooth muscle cells, fibroblasts, melanocytes, and cells of epithelioid origin.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Sphingolipid sig.ling pathway (hsa04071)
  Neuroactive ligand-receptor interaction (hsa04080)
  Efferocytosis (hsa04148)
• Reactome Pathway:
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Potential therapeutics for SARS (R-HSA-9679191)
  Lysosphingolipid and LPA receptors (R-HSA-419408)

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
FTY720-phosphate	DMDZBQH	Investigative	Sphingosine 1-phosphate receptor 1 (S1PR1) affects the binding of FTY720-phosphate.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Sphingosine 1-phosphate receptor 1 (S1PR1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sphingosine 1-phosphate receptor 1 (S1PR1).	[2]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Sphingosine 1-phosphate receptor 1 (S1PR1).	[4]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Sphingosine 1-phosphate receptor 1 (S1PR1).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Sphingosine 1-phosphate receptor 1 (S1PR1).	[6]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Sphingosine 1-phosphate receptor 1 (S1PR1).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Sphingosine 1-phosphate receptor 1 (S1PR1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sphingosine 1-phosphate receptor 1 (S1PR1).	[10]
GSK618334	DMJPXZ4	Phase 1	GSK618334 decreases the activity of Sphingosine 1-phosphate receptor 1 (S1PR1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sphingosine 1-phosphate receptor 1 (S1PR1).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sphingosine 1-phosphate receptor 1 (S1PR1).	[13]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Sphingosine 1-phosphate receptor 1 (S1PR1).	[14]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the expression of Sphingosine 1-phosphate receptor 1 (S1PR1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Sphingosine 1-phosphate receptor 1 (S1PR1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sphingosine 1-phosphate receptor 1 (S1PR1).	[9]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [4] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [5] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [6] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [7] Prostacyclin induction by high-density lipoprotein (HDL) in vascular smooth muscle cells depends on sphingosine 1-phosphate receptors: effect of simvastatin. Thromb Haemost. 2008 Jul;100(1):119-26.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] Ceramide in the molecular mechanisms of neuronal cell death. The role of sphingosine-1-phosphate. Mol Neurobiol. 2014 Aug;50(1):26-37. doi: 10.1007/s12035-013-8606-4. Epub 2014 Jan 14.
• [12] 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.
• [13] 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.
• [14] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [15] Structural insights into sphingosine-1-phosphate receptor activation. Proc Natl Acad Sci U S A. 2022 Apr 19;119(16):e2117716119. doi: 10.1073/pnas.2117716119. Epub 2022 Apr 11.