Details of the Drug Combination

General Information of Drug Combination (ID: DC30EH3)

• Drug Combination Name: Sumatriptan + Clopidogrel
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Sumatriptan (DMVYXR8): Small molecular drug
  Clopidogrel (DMOL54H): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 6.14
  Bliss Independence Score: 6.14
  Loewe Additivity Score: 19.4
  LHighest Single Agent (HSA) Score: 19.4

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sumatriptan

Disease Entry	ICD 11	Status	REF
Cluster headache	8A81.0	Approved	[2]
Migraine	8A80	Approved	[3]
Migraine disorder	N.A.	Approved	[2]

Sumatriptan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
5-HT 1D receptor (HTR1D)	TT6MSOK	5HT1D_HUMAN	Agonist	[7]

Sumatriptan Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[9]

Sumatriptan Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Decreases Expression	[10]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Decreases Expression	[11]
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3)	OTA6HYBA	GBB3_HUMAN	Increases Response	[12]
5-hydroxytryptamine receptor 1F (HTR1F)	OTALAXPA	5HT1F_HUMAN	Increases ADR	[13]

Indication(s) of Clopidogrel

Disease Entry	ICD 11	Status	REF
Acute coronary syndrome	BA41	Approved	[4]
Atherosclerosis	BD40	Approved	[4]
Myocardial infarction	BA41-BA43	Approved	[4]
Thrombosis	DB61-GB90	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[6]
Intracranial embolism	8B22.1	Investigative	[4]

Clopidogrel Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
P2Y purinoceptor 12 (P2RY12)	TTZ1DT0	P2Y12_HUMAN	Antagonist	[14]

Clopidogrel Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[15]

Clopidogrel Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[16]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[17]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[18]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[18]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[19]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[20]

Clopidogrel Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[15]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases ADR	[21]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Decreases Expression	[22]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[23]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Increases Expression	[23]
Phosphoenolpyruvate carboxykinase, cytosolic (PCK1)	OTNWEJ5Y	PCKGC_HUMAN	Increases Expression	[22]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Decreases Expression	[22]
Tight junction protein ZO-1 (TJP1)	OTBDCUPK	ZO1_HUMAN	Decreases Expression	[24]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Affects Localization	[22]
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Decreases Expression	[24]
Thyroid hormone-inducible hepatic protein (THRSP)	OTKYE01L	THRSP_HUMAN	Increases Expression	[22]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Sumatriptan FDA Label
• [3] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 54).
• [4] Clopidogrel FDA Label
• [5] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7150).
• [6] Preventing Cardiac Complication of COVID-19 Disease With Early Acute Coronary Syndrome Therapy: A Randomised Controlled Trial. (C-19-ACS)
• [7] Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. Drugs. 2001;61(3):317-32.
• [8] HT29-MTX and Caco-2/TC7 monolayers as predictive models for human intestinal absorption: role of the mucus layer. J Pharm Sci. 2001 Oct;90(10):1608-19. Comparative Study
• [9] Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J Med Chem. 2013 Sep 26;56(18):7232-42.
• [10] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [11] The effects of oral sumatriptan, a 5-HT1 receptor agonist, on circulating ACTH and cortisol concentrations in man. Br J Clin Pharmacol. 1995 Apr;39(4):389-95. doi: 10.1111/j.1365-2125.1995.tb04467.x.
• [12] G protein beta3 polymorphism and triptan response in cluster headache. Clin Pharmacol Ther. 2007 Oct;82(4):396-401. doi: 10.1038/sj.clpt.6100159. Epub 2007 Mar 14.
• [13] 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.
• [14] P2Y12, a new platelet ADP receptor, target of clopidogrel. Semin Vasc Med. 2003 May;3(2):113-22.
• [15] Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther. 2006 Nov;80(5):486-501.
• [16] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [17] Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet. 2015 Feb;54(2):147-66.
• [18] Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007 May;81(5):735-41.
• [19] Clopidogrel pathway. Pharmacogenet Genomics. 2010 Jul;20(7):463-5.
• [20] Impact of the CYP2C19 gene polymorphism on clopidogrel personalized drug regimen and the clinical outcomes. Clin Lab. 2016 Sep 1;62(9):1773-1780.
• [21] Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013 Sep;94(3):317-23. doi: 10.1038/clpt.2013.105. Epub 2013 May 22.
• [22] Identification of novel agonists by high-throughput screening and molecular modelling of human constitutive androstane receptor isoform 3. Arch Toxicol. 2019 Aug;93(8):2247-2264. doi: 10.1007/s00204-019-02495-6. Epub 2019 Jul 16.
• [23] Clopidogrel increases expression of chemokines in peripheral blood mononuclear cells in patients with coronary artery disease: results of a double-blind placebo-controlled study. J Thromb Haemost. 2006 Oct;4(10):2140-7. doi: 10.1111/j.1538-7836.2006.02131.x. Epub 2006 Jul 17.
• [24] Attenuated expression of the tight junction proteins is involved in clopidogrel-induced gastric injury through p38 MAPK activation. Toxicology. 2013 Feb 8;304:41-8. doi: 10.1016/j.tox.2012.11.020. Epub 2012 Dec 7.