Details of the Drug Combination

General Information of Drug Combination (ID: DCWOJV5)

• Drug Combination Name: Norcisapride + Atovaquone
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Norcisapride (DMJSKUI): Small molecular drug
  Atovaquone (DMY4UMW): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 2.49
  Bliss Independence Score: 2.49
  Loewe Additivity Score: 15.5
  LHighest Single Agent (HSA) Score: 15.52

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Norcisapride

Disease Entry	ICD 11	Status	REF
Gastroesophageal reflux disease	DA22.Z	Discontinued in Phase 2	[2]

Norcisapride Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
5-HT 4 receptor (HTR4)	TT07C3Y	5HT4R_HUMAN	Inhibitor	[4]
5-HT 3A receptor (HTR3A)	TTPC4TU	5HT3A_HUMAN	Inhibitor	[4]

Norcisapride Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[5]

Norcisapride Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Affects Chemical Synthesis	[5]

Indication(s) of Atovaquone

Disease Entry	ICD 11	Status	REF
Fungal infection	1F29-1F2F	Approved	[3]

Atovaquone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Plasmodium Dihydroorotate dehydrogenase (Malaria DHOdehase)	TT3PQ2Y	PYRD_PLAF7	Inhibitor	[6]

Atovaquone Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]

Atovaquone Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Dihydroorotate dehydrogenase (DHODH)	OTAKFN78	PYRD_HUMAN	Decreases Activity	[8]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Activity	[9]

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] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007174)
• [3] The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
• [4] mu-Opioid/5-HT4 dual pharmacologically active agents-efforts towards an effective opioid analgesic with less GI and respiratory side effects (Part I). Bioorg Med Chem Lett. 2009 Oct 1;19(19):5679-83.
• [5] Cytochrome P450 Involvement in the biotransformation of cisapride and racemic norcisapride in vitro: differential activity of individual human CYP3A isoforms. Drug Metab Dispos. 2001 Dec;29(12):1548-54.
• [6] Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain. Protein Sci. 2004 Apr;13(4):1031-42.
• [7] Time-dependent pharmacokinetics and drug metabolism of atovaquone plus proguanil (Malarone) when taken as chemoprophylaxis. Eur J Clin Pharmacol. 2002 Apr;58(1):19-27.
• [8] Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Chem Biol Interact. 2000 Jan 3;124(1):61-76.
• [9] Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5.