Details of the Drug Combination

General Information of Drug Combination (ID: DCY86ZW)

• Drug Combination Name: Pyrimethamine + Miconazole
• Indication: Hepatoblastoma; Status: Investigative [1]
• Component Drugs:
  Pyrimethamine (DM5X7VY): Small molecular drug
  Miconazole (DMPMYE8): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HB3
  Zero Interaction Potency (ZIP) Score: 1.491
  Bliss Independence Score: 6.802
  Loewe Additivity Score: 0.11
  LHighest Single Agent (HSA) Score: 5.022

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pyrimethamine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[2]

Pyrimethamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Folate receptor alpha (FOLR1)	TTVC37M	FOLR1_HUMAN	Modulator	[5]

Pyrimethamine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[6]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[7]

Pyrimethamine Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Decreases Activity	[8]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[9]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[10]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[11]

Indication(s) of Miconazole

Disease Entry	ICD 11	Status	REF
Cutaneous candidiasis	1F23.14	Approved	[3]
Fungal infection	1F29-1F2F	Approved	[4]
Mycoses	1F2Z	Approved	[3]
Onychomycosis	EE12.1	Approved	[3]
Tinea corporis	1F28.Y	Approved	[3]
Tinea cruris	1F28.3	Approved	[3]
Tinea versicolor	1F2D.0	Approved	[3]
Tinea pedis	1F28.2	Investigative	[3]

Miconazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Candida Cytochrome P450 51 (Candi ERG11)	TTTSOUD	CP51_CANAL	Modulator	[5]

Miconazole Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]

Miconazole 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	Decreases Expression	[13]
Tyrosine aminotransferase (TAT)	OT2CJ91O	ATTY_HUMAN	Decreases Expression	[13]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Decreases Expression	[13]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[14]
Adenylate cyclase type 9 (ADCY9)	OT1IZT5K	ADCY9_HUMAN	Increases Activity	[15]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Lipidation	[16]

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: 4800).
• [3] Miconazole FDA Label
• [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. (Ligand id: 2449).
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [6] Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34.
• [7] Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity. Drug Metab Dispos. 2018 May;46(5):592-599.
• [8] Interactions between Oroxylin A with the solute carrier transporters and ATP-binding cassette transporters: Drug transporters profile for this flavonoid. Chem Biol Interact. 2020 Jun 1;324:109097. doi: 10.1016/j.cbi.2020.109097. Epub 2020 Apr 16.
• [9] Selection of drugs to test the specificity of the Tg.AC assay by screening for induction of the gadd153 promoter in vitro. Toxicol Sci. 2003 Aug;74(2):260-70. doi: 10.1093/toxsci/kfg113. Epub 2003 May 2.
• [10] Antifolate activity of pyrimethamine enhances temozolomide-induced cytotoxicity in melanoma cells. Mol Cancer Res. 2009 May;7(5):703-12. doi: 10.1158/1541-7786.MCR-08-0263. Epub 2009 May 12.
• [11] 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.
• [12] Inhibition of cytochrome P450 enzymes participating in p-nitrophenol hydroxylation by drugs known as CYP2E1 inhibitors. Chem Biol Interact. 2004 Apr 15;147(3):331-40.
• [13] Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor. Mol Pharmacol. 2006 Jul;70(1):329-39.
• [14] In vitro inhibitory effects of asiaticoside and madecassoside on human cytochrome P450. Toxicol In Vitro. 2011 Jun;25(4):890-6.
• [15] Direct stimulation of adenylyl cyclase 9 by the fungicide imidazole miconazole. Naunyn Schmiedebergs Arch Pharmacol. 2019 Apr;392(4):497-504. doi: 10.1007/s00210-018-01610-1. Epub 2019 Jan 3.
• [16] Miconazole induces protective autophagy in bladder cancer cells. Environ Toxicol. 2021 Feb;36(2):185-193. doi: 10.1002/tox.23024. Epub 2020 Sep 27.