Details of the Drug Combination

General Information of Drug Combination (ID: DC69LEJ)

• Drug Combination Name: Bepridil + Isosorbide Dinitrate
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Bepridil (DM0RKS4): Small molecular drug
  Isosorbide Dinitrate (DMBI4JG): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 12.74
  Bliss Independence Score: 12.74
  Loewe Additivity Score: 25.13
  LHighest Single Agent (HSA) Score: 25.14

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Bepridil

Disease Entry	ICD 11	Status	REF
Chronic/stable angina	BA40.1	Approved	[2]

Bepridil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Calcium channel unspecific (CaC)	TT5HONZ	NOUNIPROTAC	Modulator	[5]

Bepridil Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]

Bepridil Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[8]

Bepridil Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[9]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[9]
Potassium voltage-gated channel subfamily A member 5 (KCNA5)	OTHI2N71	KCNA5_HUMAN	Decreases Activity	[10]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[9]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Increases Response To Substance	[9]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[11]
Eukaryotic translation initiation factor 2A (EIF2A)	OTWXELQP	EIF2A_HUMAN	Increases Phosphorylation	[9]

Indication(s) of Isosorbide Dinitrate

Disease Entry	ICD 11	Status	REF
Anal fissure	DB50.0	Approved	[3]
Angina pectoris	BA40	Approved	[3]
Chronic heart failure	BD1Z	Approved	[4]

Isosorbide Dinitrate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Guanylate cyclase (GC)	TT6HPVC	NOUNIPROTAC	Stimulator	[12]

Isosorbide Dinitrate Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[14]

Isosorbide Dinitrate Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[15]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Decreases Response To Substance	[16]

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: 2337).
• [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: 7051).
• [4] Isosorbide dinitrate FDA Label
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [6] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [7] Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17.
• [8] Serum flecainide S/R ratio reflects the CYP2D6 genotype and changes in CYP2D6 activity. Drug Metab Pharmacokinet. 2015 Aug;30(4):257-62.
• [9] Amiodarone sensitizes human glioma cells but not astrocytes to TRAIL-induced apoptosis via CHOP-mediated DR5 upregulation. Neuro Oncol. 2011 Mar;13(3):267-79. doi: 10.1093/neuonc/noq195. Epub 2011 Feb 3.
• [10] Inhibitory effect of bepridil on hKv1.5 channel current: comparison with amiodarone and E-4031. Eur J Pharmacol. 2001 Nov 2;430(2-3):149-57. doi: 10.1016/s0014-2999(01)01381-4.
• [11] Automated tight seal electrophysiology for assessing the potential hERG liability of pharmaceutical compounds. Assay Drug Dev Technol. 2004 Oct;2(5):497-506. doi: 10.1089/adt.2004.2.497.
• [12] Nitric oxide and nitric oxide synthase isoforms in the normal, hypertrophic, and failing heart. Mol Cell Biochem. 2010 Jan;333(1-2):191-201.
• [13] Isoforms of cytochrome P450 on organic nitrate-derived nitric oxide release in human heart vessels. FEBS Lett. 1999 Jun 11;452(3):165-9.
• [14] Nitroglycerin and isosorbide dinitrate stimulation of glutathione disulfide efflux from perfused rat liver. Biochem Pharmacol. 1989 Nov 1;38(21):3807-10.
• [15] 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.
• [16] Isosorbide dinitrate-induced hemolysis in G6PD-deficient subjects. Acta Haematol. 1983;69(1):63-4. doi: 10.1159/000206844.