Details of the Drug Combination

General Information of Drug Combination (ID: DC88KKL)

• Drug Combination Name: benzamil + Piperaquine
• Indication: DD2; Status: Investigative [1]
• Component Drugs:
  benzamil (DM57SVW): Small molecular drug
  Piperaquine (DMT70RC): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DD2
  Zero Interaction Potency (ZIP) Score: 3.521
  Bliss Independence Score: 3.363
  Loewe Additivity Score: 1.415
  LHighest Single Agent (HSA) Score: 1.184

Molecular Interaction Atlas of This Drug Combination

Indication(s) of benzamil

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[2]

benzamil Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Polycystic kidney disease 2-like 1 (TRPP2)	TTAHD89	PK2L1_HUMAN	Blocker (channel blocker)	[4]
Amiloride-sensitive sodium channel (ENaC)	TTQM7TE	SCNNA_HUMAN; SCNNB_HUMAN; SCNNG_HUMAN; SCNND_HUMAN	Blocker (channel blocker)	[5]
Acid-sensing ion channel 3 (ASIC3)	TTLGDIS	ASIC3_HUMAN	Blocker (channel blocker)	[6]

benzamil Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[7]

benzamil Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Secretin (SCT)	OTV3MLOO	SECR_HUMAN	Decreases Activity	[8]
Diamine oxidase (AOC1)	OTRC220K	AOC1_HUMAN	Affects Binding	[9]
Hepcidin (HAMP)	OT607RBL	HEPC_HUMAN	Decreases Expression	[10]
Sodium/hydrogen exchanger 7 (SLC9A7)	OTVDLTYA	SL9A7_HUMAN	Decreases Activity	[11]

Indication(s) of Piperaquine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[3]

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	[3]

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	[12]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[13]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [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: 4145).
• [3] The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
• [4] 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. (Target id: 505).
• [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. (Target id: 742).
• [6] 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. (Target id: 684).
• [7] 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.
• [8] Activation of transepithelial ion transport by secretin in human intestinal Caco-2 cells. Jpn J Physiol. 2000 Apr;50(2):215-25. doi: 10.2170/jjphysiol.50.215.
• [9] Human kidney amiloride-binding protein: cDNA structure and functional expression. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7347-51. doi: 10.1073/pnas.87.19.7347.
• [10] A HAMP promoter bioassay system for identifying chemical compounds that modulate hepcidin expression. Exp Hematol. 2015 May;43(5):404-413.e5. doi: 10.1016/j.exphem.2015.01.005. Epub 2015 Jan 26.
• [11] Molecular cloning and characterization of a novel (Na+,K+)/H+ exchanger localized to the trans-Golgi network. J Biol Chem. 2001 May 18;276(20):17387-94. doi: 10.1074/jbc.M101319200. Epub 2001 Feb 26.
• [12] Eurartesim - European Medicines Agency
• [13] Open-label crossover study of primaquine and dihydroartemisinin-piperaquine pharmacokinetics in healthy adult thai subjects. Antimicrob Agents Chemother. 2014 Dec;58(12):7340-6.