Details of the Drug Combination

General Information of Drug Combination (ID: DC1W2W5)

• Drug Combination Name: Atovaquone + Methylene blue
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Atovaquone (DMY4UMW): Small molecular drug
  Methylene blue (DMJAPE7): N.A.
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 4.83
  Bliss Independence Score: 4.83
  Loewe Additivity Score: 5.53
  LHighest Single Agent (HSA) Score: 5.55

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Atovaquone

Disease Entry	ICD 11	Status	REF
Fungal infection	1F29-1F2F	Approved	[2]

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	[5]

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	[6]

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	[7]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Activity	[8]

Indication(s) of Methylene blue

Disease Entry	ICD 11	Status	REF
Acquired methemoglobinemia	3A93	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]

Methylene blue Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Monoamine oxidase (MAO)	TT32XQJ	NOUNIPROTAC	.	[9]
Guanylate cyclase (GC)	TT6HPVC	NOUNIPROTAC	Inhibitor	[10]

Methylene blue Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Amine oxidase B (MAOB)	OTTDFM1O	AOFB_HUMAN	Decreases Activity	[11]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[12]
Microtubule-associated protein tau (MAPT)	OTMTP2Z7	TAU_HUMAN	Increases Expression	[13]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Increases Activity	[14]
Acetylcholinesterase (ACHE)	OT2H8HG6	ACES_HUMAN	Decreases Activity	[15]
6-phosphogluconate dehydrogenase, decarboxylating (PGD)	OTVG296F	6PGD_HUMAN	Increases Activity	[14]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases ADR	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Hepatoblastoma	DC75D6M	HB3	Investigative	[1]

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] The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
• [3] Recombinant Plasmodium falciparum glutathione reductase is inhibited by the antimalarial dye methylene blue. FEBS Lett. 1998 Feb 6;422(3):311-4.
• [4] ClinicalTrials.gov (NCT04370288) Clinical Application of Methylene Blue for Treatment of Covid-19 Patients. U.S. National Institutes of Health.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Photoluminescence of CdTe nanocrystals modulated by methylene blue and DNA. A label-free luminescent signaling nanohybrid platform. Phys Chem Chem Phys. 2009 Jul 7;11(25):5062-9.
• [10] Curcumin ameliorates high glucose-induced acute vascular endothelial dysfunction in rat thoracic aorta. Clin Exp Pharmacol Physiol. 2009 Dec;36(12):1177-82.
• [11] Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors. Food Chem Toxicol. 2011 Aug;49(8):1773-81.
• [12] Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation. Arch Toxicol. 2022 Jul;96(7):1975-1987. doi: 10.1007/s00204-022-03291-5. Epub 2022 Apr 18.
• [13] Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression. Mol Neurodegener. 2006 Jul 26;1:6. doi: 10.1186/1750-1326-1-6.
• [14] Defenses against oxidation in human erythrocytes: role of glutathione reductase in the activation of glucose decarboxylation by hemolytic drugs. J Lab Clin Med. 1991 Apr;117(4):325-31.
• [15] Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition. Environ Health Perspect. 2021 Apr;129(4):47008. doi: 10.1289/EHP6993. Epub 2021 Apr 12.
• [16] 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.