Details of the Drug Combination

General Information of Drug Combination (ID: DCTEVAT)

• Drug Combination Name: Topiramate + Piperaquine
• Indication: DD2; Status: Investigative [1]
• Component Drugs:
  Topiramate (DM82Z30): Small molecular drug
  Piperaquine (DMT70RC): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DD2
  Zero Interaction Potency (ZIP) Score: 2.837
  Bliss Independence Score: 4.119
  Loewe Additivity Score: 1.88
  LHighest Single Agent (HSA) Score: 2.465

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Topiramate

Disease Entry	ICD 11	Status	REF
Alcohol dependence	6C40.2	Approved	[2]
Epilepsy	8A60-8A68	Approved	[2]
Epilepsy with generalized tonic-clonic seizures	N.A.	Approved	[3]
Hyperlipidemia	5C80.Z	Approved	[3]
Hypertriglyceridemia	5C80.1	Approved	[3]
Obesity	5B81	Approved	[3]
Metabolic syndrome x	5C50-5D2Z	Investigative	[3]
Seizure disorder	8A6Z	Investigative	[4]

Topiramate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glutamate receptor ionotropic kainate 1 (GRIK1)	TT0MYE2	GRIK1_HUMAN	Antagonist	[7]

Topiramate Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]

Topiramate Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]

Topiramate Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[9]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2)	OT02MSKN	3BHS2_HUMAN	Decreases Activity	[10]
Carbonic anhydrase 12 (CA12)	OT6WNFU8	CAH12_HUMAN	Decreases Activity	[11]
HLA class II histocompatibility antigen, DM beta chain (HLA-DMB)	OT17HGXJ	DMB_HUMAN	Affects Expression	[12]
Pro-neuropeptide Y (NPY)	OT4ICV3P	NPY_HUMAN	Increases ADR	[13]
Galanin peptides (GAL)	OTB3VPTO	GALA_HUMAN	Increases ADR	[13]

Indication(s) of Piperaquine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[5]

Piperaquine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Sarcoplasmic/endoplasmic reticulum calcium ATPase (ATP2A)	TTZVSJ2	NOUNIPROTAC	Inhibitor	[5]

Piperaquine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[14]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[15]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] 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: 6849).
• [3] Topiramate FDA Label
• [4] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [5] The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
• [6] The association between the C802T polymorphism of the UDP-glucuronosyltransferase 2B7 gene and effective topiramate dosage. Zh Nevrol Psikhiatr Im S S Korsakova. 2007;107(5):63-4.
• [7] Development of medications for alcohol use disorders: recent advances and ongoing challenges. Expert Opin Emerg Drugs. 2005 May;10(2):323-43.
• [8] The antiepileptic drug topiramate is a substrate for human P-glycoprotein but not multidrug resistance proteins. Pharm Res. 2009 Nov;26(11):2464-70.
• [9] Dose-dependent induction of cytochrome P450 (CYP) 3A4 and activation of pregnane X receptor by topiramate. Epilepsia. 2003 Dec;44(12):1521-8.
• [10] Effects of anticonvulsants on human p450c17 (17alpha-hydroxylase/17,20 lyase) and 3beta-hydroxysteroid dehydrogenase type 2. Epilepsia. 2005 Mar;46(3):444-8.
• [11] Design, synthesis, and biological evaluation of novel carbohydrate-based sulfamates as carbonic anhydrase inhibitors. J Med Chem. 2011 Mar 10;54(5):1481-9.
• [12] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [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] Eurartesim - European Medicines Agency
• [15] Open-label crossover study of primaquine and dihydroartemisinin-piperaquine pharmacokinetics in healthy adult thai subjects. Antimicrob Agents Chemother. 2014 Dec;58(12):7340-6.