Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWR90PK)

• DOT Name: P-selectin (SELP)
• Synonyms: CD62 antigen-like family member P; Granule membrane protein 140; GMP-140; Leukocyte-endothelial cell adhesion molecule 3; LECAM3; Platelet activation dependent granule-external membrane protein; PADGEM; CD antigen CD62P
• Gene Name: SELP
• UniProt ID: LYAM3_HUMAN
• PDB ID: 1FSB; 1G1Q; 1G1R; 1G1S; 1HES
• Pfam ID: PF00059 ; PF00084
• Sequence:
  MANCQIAILYQRFQRVVFGISQLLCFSALISELTNQKEVAAWTYHYSTKAYSWNISRKYC
  QNRYTDLVAIQNKNEIDYLNKVLPYYSSYYWIGIRKNNKTWTWVGTKKALTNEAENWADN
  EPNNKRNNEDCVEIYIKSPSAPGKWNDEHCLKKKHALCYTASCQDMSCSKQGECLETIGN
  YTCSCYPGFYGPECEYVRECGELELPQHVLMNCSHPLGNFSFNSQCSFHCTDGYQVNGPS
  KLECLASGIWTNKPPQCLAAQCPPLKIPERGNMTCLHSAKAFQHQSSCSFSCEEGFALVG
  PEVVQCTASGVWTAPAPVCKAVQCQHLEAPSEGTMDCVHPLTAFAYGSSCKFECQPGYRV
  RGLDMLRCIDSGHWSAPLPTCEAISCEPLESPVHGSMDCSPSLRAFQYDTNCSFRCAEGF
  MLRGADIVRCDNLGQWTAPAPVCQALQCQDLPVPNEARVNCSHPFGAFRYQSVCSFTCNE
  GLLLVGASVLQCLATGNWNSVPPECQAIPCTPLLSPQNGTMTCVQPLGSSSYKSTCQFIC
  DEGYSLSGPERLDCTRSGRWTDSPPMCEAIKCPELFAPEQGSLDCSDTRGEFNVGSTCHF
  SCDNGFKLEGPNNVECTTSGRWSATPPTCKGIASLPTPGVQCPALTTPGQGTMYCRHHPG
  TFGFNTTCYFGCNAGFTLIGDSTLSCRPSGQWTAVTPACRAVKCSELHVNKPIAMNCSNL
  WGNFSYGSICSFHCLEGQLLNGSAQTACQENGHWSTTVPTCQAGPLTIQEALTYFGGAVA
  STIGLIMGGTLLALLRKRFRQKDDGKCPLNPHSHLGTYGVFTNAAFDPSP
• Function: Ca(2+)-dependent receptor for myeloid cells that binds to carbohydrates on neutrophils and monocytes. Mediates the interaction of activated endothelial cells or platelets with leukocytes. The ligand recognized is sialyl-Lewis X. Mediates rapid rolling of leukocyte rolling over vascular surfaces during the initial steps in inflammation through interaction with SELPLG.
• Tissue Specificity: Stored in the alpha-granules of platelets and Weibel-Palade bodies of endothelial cells. Upon cell activation by agonists, P-selectin is transported rapidly to the cell surface.
• KEGG Pathway:
  Cell adhesion molecules (hsa04514)
  Neutrophil extracellular trap formation (hsa04613)
  Malaria (hsa05144)
  Staphylococcus aureus infection (hsa05150)
  Coro.virus disease - COVID-19 (hsa05171)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Cell surface interactions at the vascular wall (R-HSA-202733)
  Platelet degranulation (R-HSA-114608)

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
Indomethacin	DMSC4A7	Approved	P-selectin (SELP) increases the Gastric disorder ADR of Indomethacin.	[19]
Methylprednisolone	DM4BDON	Approved	P-selectin (SELP) increases the Idiopathic thrombocytopenic purpura ADR of Methylprednisolone.	[19]
LXA4	DMGSVL0	Investigative	P-selectin (SELP) affects the response to substance of LXA4.	[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 P-selectin (SELP).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of P-selectin (SELP).	[12]

17 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 P-selectin (SELP).	[2]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of P-selectin (SELP).	[3]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of P-selectin (SELP).	[4]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of P-selectin (SELP).	[5]
Sertraline	DM0FB1J	Approved	Sertraline decreases the expression of P-selectin (SELP).	[7]
Ardeparin	DMYRX8B	Approved	Ardeparin increases the expression of P-selectin (SELP).	[8]
Cimetidine	DMH61ZB	Approved	Cimetidine decreases the expression of P-selectin (SELP).	[9]
Amlodipine	DMBDAZV	Approved	Amlodipine decreases the expression of P-selectin (SELP).	[10]
Asasantin	DMCZIHT	Approved	Asasantin decreases the expression of P-selectin (SELP).	[11]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of P-selectin (SELP).	[13]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid increases the expression of P-selectin (SELP).	[14]
Fmet-leu-phe	DMQ391A	Investigative	Fmet-leu-phe increases the expression of P-selectin (SELP).	[15]
PAF	DMRZAQW	Investigative	PAF increases the expression of P-selectin (SELP).	[15]
Anandamide	DMCKH3P	Investigative	Anandamide increases the expression of P-selectin (SELP).	[16]
adenosine diphosphate	DMFUHKP	Investigative	adenosine diphosphate increases the expression of P-selectin (SELP).	[17]
LTC4	DM702WR	Investigative	LTC4 increases the expression of P-selectin (SELP).	[18]
LTD4	DMIUZX3	Investigative	LTD4 increases the expression of P-selectin (SELP).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cocaine	DMSOX7I	Approved	Cocaine affects the localization of P-selectin (SELP).	[6]

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] 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] Hemostatic abnormalities associated with acute promyelocytic leukemia and corrective effects of all-trans-retinoic acid or arsenic trioxide treatment. Chin Med J (Engl). 2000 Mar;113(3):236-40.
• [4] Reduced plaque formation induced by rosiglitazone in an STZ-diabetes mouse model of atherosclerosis is associated with downregulation of adhesion molecules. Atherosclerosis. 2008 Jul;199(1):55-64. doi: 10.1016/j.atherosclerosis.2007.10.038. Epub 2008 Feb 21.
• [5] Lack of uniform platelet activation in patients after ischemic stroke and choice of antiplatelet therapy. Thromb Res. 2004;113(3-4):197-204. doi: 10.1016/j.thromres.2004.03.002.
• [6] Cocaine activates platelets and increases the formation of circulating platelet containing microaggregates in humans. Heart. 2000 Jun;83(6):688-95. doi: 10.1136/heart.83.6.688.
• [7] Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation. 2003 Aug 26;108(8):939-44. doi: 10.1161/01.CIR.0000085163.21752.0A. Epub 2003 Aug 11.
• [8] A flow cytometric assay of platelet activation marker P-selectin (CD62P) distinguishes heparin-induced thrombocytopenia (HIT) from HIT with thrombosis (HITT). Thromb Haemost. 1999 Oct;82(4):1255-9.
• [9] Effects of histamine 2 receptor antagonists on endothelial-neutrophil adhesion and surface expression of endothelial adhesion molecules induced by high glucose levels. J Diabetes Complications. 2007 Jan-Feb;21(1):50-5. doi: 10.1016/j.jdiacomp.2006.02.002.
• [10] Platelet morphology and plasma indices of platelet activation in essential hypertension: effects of amlodipine-based antihypertensive therapy. Ann Med. 2004;36(7):552-7. doi: 10.1080/07853890410017386.
• [11] Magnitude and time course of platelet inhibition with Aggrenox and Aspirin in patients after ischemic stroke: the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial. Eur J Pharmacol. 2004 Sep 24;499(3):315-24. doi: 10.1016/j.ejphar.2004.07.114.
• [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] Acetaldehyde stimulates monocyte adhesion in a P-selectin- and TNFalpha-dependent manner. Atherosclerosis. 2009 Jun;204(2):372-80. doi: 10.1016/j.atherosclerosis.2008.10.008. Epub 2008 Oct 18.
• [14] Inhibition of platelet GPIIb-IIIa and P-selectin expression by aspirin is impaired by stress hyperglycemia. J Diabetes Complications. 2009 Jan-Feb;23(1):65-70. doi: 10.1016/j.jdiacomp.2007.06.003. Epub 2008 Apr 16.
• [15] Platelet-leukocyte cross talk in whole blood. Arterioscler Thromb Vasc Biol. 2000 Dec;20(12):2702-8. doi: 10.1161/01.atv.20.12.2702.
• [16] Differential effects of endogenous, phyto and synthetic cannabinoids on thrombogenesis and platelet activity. Biofactors. 2016 Nov 12;42(6):581-590. doi: 10.1002/biof.1294. Epub 2016 May 6.
• [17] Inhibition of platelet-mediated arterial thrombosis and platelet granule exocytosis by 3',4'-dihydroxyflavonol and quercetin. Platelets. 2013;24(8):594-604. doi: 10.3109/09537104.2012.749396. Epub 2012 Dec 18.
• [18] Cysteinyl leukotrienes induce P-selectin expression in human endothelial cells via a non-CysLT1 receptor-mediated mechanism. J Pharmacol Exp Ther. 1997 May;281(2):655-62.
• [19] 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.
• [20] Mechanisms for lipoxin A4-induced neutrophil-dependent cytotoxicity for human endothelial cells. J Lab Clin Med. 1995 Jul;126(1):36-43.