Details of the Drug Combination

General Information of Drug Combination (ID: DCEOT0X)

Drug Combination Name

Diazoxide Dronedarone

Indication

Disease Entry	Status	REF
Chronic myelogenous leukemia	Investigative	[1]

Component Drugs

Diazoxide DML1538

Dronedarone DMA8FS5

Small molecular drug

2D MOL

3D MOL

High-throughput Screening Result

Testing Cell Line: KBM-7

Zero Interaction Potency (ZIP) Score: 1.28

Bliss Independence Score: 1.28

Loewe Additivity Score: 1.68

LHighest Single Agent (HSA) Score: 1.68

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

Indication(s) of Diazoxide

Disease Entry	ICD 11	Status	REF
Congenital hyperinsulinism	5A4Y	Approved	[2]
Hyperinsulinemia	5A4Y	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Hypertensive emergency	BA03	Approved	[2]
Insulinoma	2C10.1	Approved	[2]
Malignant essential hypertension	BA00	Approved	[2]

Diazoxide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Potassium channel unspecific (KC)	TT1VOHK	NOUNIPROTAC	Modulator	[5]
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Diazoxide Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[6]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[6]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Activity	[7]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Secretion	[6]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[8]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[8]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Increases Expression	[7]
ATP-sensitive inward rectifier potassium channel 11 (KCNJ11)	OTPUUELV	KCJ11_HUMAN	Decreases Expression	[9]
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⏷ Show the Full List of 8 DOT(s)

Indication(s) of Dronedarone

Disease Entry	ICD 11	Status	REF
Angina pectoris	BA40	Approved	[4]
Atrial fibrillation	BC81.3	Withdrawn from market	[4]

Dronedarone Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated potassium channel Kv1.5 (KCNA5)	TTW0CMT	KCNA5_HUMAN	Blocker	[10]
Potassium channel unspecific (KC)	TT1VOHK	NOUNIPROTAC	Inhibitor	[11]
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Dronedarone Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[13]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[14]
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Dronedarone Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Response To Substance	[15]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Response To Substance	[15]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Decreases Response To Substance	[15]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[16]
DNA topoisomerase 2-alpha (TOP2A)	OT6LPS08	TOP2A_HUMAN	Decreases Expression	[15]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Expression	[15]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[15]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[15]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Expression	[15]
G1/S-specific cyclin-D3 (CCND3)	OTNKPQ22	CCND3_HUMAN	Decreases Expression	[15]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[16]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[16]
Cyclin-dependent kinase 6 (CDK6)	OTR95N0X	CDK6_HUMAN	Decreases Expression	[15]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[17]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[18]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Metabolism	[15]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Metabolism	[15]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Increases Metabolism	[15]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Metabolism	[15]
Cytochrome P450 3A7 (CYP3A7)	OTTCDHHM	CP3A7_HUMAN	Increases Metabolism	[15]
Cytochrome P450 2C18 (CYP2C18)	OTY687L9	CP2CI_HUMAN	Increases Metabolism	[15]
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⏷ Show the Full List of 21 DOT(s)

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	Diazoxide FDA Label
3	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: 2409).
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: 7465).
5	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
6	Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy. J Hypertens. 2006 May;24(5):915-22. doi: 10.1097/01.hjh.0000222762.84605.03.
7	Diazoxide-mediated preconditioning against apoptosis involves activation of cAMP-response element-binding protein (CREB) and NFkappaB. J Biol Chem. 2004 Nov 5;279(45):46748-54. doi: 10.1074/jbc.M406217200. Epub 2004 Aug 23.
8	Diazoxide-mediated growth inhibition in human lung cancer cells via downregulation of beta-catenin-mediated cyclin D1 transcription. Lung. 2009 Jan-Feb;187(1):61-7. doi: 10.1007/s00408-008-9127-1. Epub 2008 Dec 4.
9	Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats. Toxicol Appl Pharmacol. 2013 Feb 1;266(3):375-84. doi: 10.1016/j.taap.2012.11.015. Epub 2012 Nov 28.
10	New antiarrhythmic agents for atrial fibrillation and atrial flutter. Expert Opin Emerg Drugs. 2005 May;10(2):311-22.
11	Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
12	Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin Drug Saf. 2012 Nov;11(6):1023-45.
13	Effect of dronedarone on the pharmacokinetics of carvedilol following oral administration to rats. Eur J Pharm Sci. 2018 Jan 1;111:13-19.
14	Inactivation of human cytochrome P450 3A4 and 3A5 by dronedarone and N-desbutyl dronedarone. Mol Pharmacol. 2016 Jan;89(1):1-13.
15	The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone. Arch Toxicol. 2018 Jun;92(6):1969-1981. doi: 10.1007/s00204-018-2196-x. Epub 2018 Apr 3.
16	Mechanisms of hepatocellular toxicity associated with dronedarone--a comparison to amiodarone. Toxicol Sci. 2013 Feb;131(2):480-90. doi: 10.1093/toxsci/kfs298. Epub 2012 Nov 7.
17	Five novel single nucleotide polymorphisms in the CYP2C8 gene, one of which induces a frame-shift. Drug Metab Pharmacokinet. 2002;17(4):374-7. doi: 10.2133/dmpk.17.374.
18	Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.