Details of the Drug Combination

General Information of Drug Combination (ID: DCLYY4B)

• Drug Combination Name: Pentamidine + Nitrosoglutathione
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Pentamidine (DMHZJCG): Small molecular drug
  Nitrosoglutathione (DMZ9WI4): N.A.
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 14.59
  Bliss Independence Score: 14.59
  Loewe Additivity Score: 26.29
  LHighest Single Agent (HSA) Score: 26.29

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pentamidine

Disease Entry	ICD 11	Status	REF
African trypanosomiasis	1F51	Approved	[2]
Fungal infection	1F29-1F2F	Approved	[3]
Pneumocystis pneumonia	CA40.20	Approved	[2]
Human immunodeficiency virus infection	1C62	Withdrawn from market	[4]

Pentamidine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tryptase alpha/beta-1 (Tryptase)	TTM1TDX	TRYB1_HUMAN	Inhibitor	[6]

Pentamidine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[7]

Pentamidine Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[8]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[8]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[8]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[8]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[9]

Pentamidine Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[10]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[5]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[5]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[5]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[5]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[5]
Fibronectin type III domain-containing protein 4 (FNDC4)	OTOQK0WK	FNDC4_HUMAN	Increases Expression	[5]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[5]
Nibrin (NBN)	OT73B5MD	NBN_HUMAN	Affects Localization	[11]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[12]
Interferon gamma receptor 1 (IFNGR1)	OTCTQBWW	INGR1_HUMAN	Increases Expression	[13]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Affects Localization	[11]
Double-strand break repair protein MRE11 (MRE11)	OTGU8TZM	MRE11_HUMAN	Decreases Activity	[11]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Decreases Activity	[11]
Histone acetyltransferase KAT5 (KAT5)	OTL7257A	KAT5_HUMAN	Decreases Activity	[11]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Increases Activity	[14]

Nitrosoglutathione Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
S-(hydroxymethyl)glutathione dehydrogenase (adh)	DEAH3PE	A0A0A7DS01_VIBCL	Metabolism	[15]

Nitrosoglutathione Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serine protease HTRA2, mitochondrial (HTRA2)	OTC7616F	HTRA2_HUMAN	Affects Localization	[16]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Decreases Secretion	[17]
Interleukin-12 subunit beta (IL12B)	OT0JF8A3	IL12B_HUMAN	Decreases Expression	[17]
Transcription factor Sp3 (SP3)	OTYDQZ1T	SP3_HUMAN	Decreases Activity	[18]
Carbonyl reductase 1 (CBR1)	OTQ3A541	CBR1_HUMAN	Increases Reduction	[19]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Response To Substance	[20]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Pentamidine FDA Label
• [3] Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [6] Inhibitors of tryptase for the treatment of mast cell-mediated diseases. Curr Pharm Des. 1998 Oct;4(5):381-96.
• [7] Transport of dicationic drugs pentamidine and furamidine by human organic cation transporters. Drug Metab Dispos. 2009 Feb;37(2):424-30.
• [8] Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol. 2003 Sep;59(5-6):429-42.
• [9] Value of preemptive CYP2C19 genotyping in allogeneic stem cell transplant patients considered for pentamidine administration. Clin Transplant. 2011 May-Jun;25(3):E271-5.
• [10] 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.
• [11] Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation. Mol Cancer. 2010 Feb 9;9:34. doi: 10.1186/1476-4598-9-34.
• [12] 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.
• [13] Antileishmanial drugs cause up-regulation of interferon-gamma receptor 1, not only in the monocytes of visceral leishmaniasis cases but also in cultured THP1 cells. Ann Trop Med Parasitol. 2003 Apr;97(3):245-57. doi: 10.1179/000349803235001714.
• [14] Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity. Biochem Pharmacol. 2012 Jun 15;83(12):1674-81. doi: 10.1016/j.bcp.2012.02.027. Epub 2012 Mar 7.
• [15] Nitrosative stress response in Vibrio cholerae: role of S-nitrosoglutathione reductase. Appl Biochem Biotechnol. 2017 Jul;182(3):871-884.
• [16] The induction of reactive oxygen species and loss of mitochondrial Omi/HtrA2 is associated with S-nitrosoglutathione-induced apoptosis in human endothelial cells. Toxicol Appl Pharmacol. 2010 May 1;244(3):374-84. doi: 10.1016/j.taap.2010.02.004. Epub 2010 Feb 11.
• [17] Regulatory role of nitric oxide on monocyte-derived dendritic cell functions. J Interferon Cytokine Res. 2003 Aug;23(8):423-31. doi: 10.1089/107999003322277838.
• [18] Concentration-dependent effects of endogenous S-nitrosoglutathione on gene regulation by specificity proteins Sp3 and Sp1. Biochem J. 2004 May 15;380(Pt 1):67-74. doi: 10.1042/BJ20031687.
• [19] Studies on reduction of S-nitrosoglutathione by human carbonyl reductases 1 and 3. Chem Biol Interact. 2011 May 30;191(1-3):95-103.
• [20] Hypersensitivity of ataxia-telangiectasia fibroblasts to a nitric oxide donor. Free Radic Biol Med. 1997;22(1-2):343-7. doi: 10.1016/s0891-5849(96)00336-x.