Details of the Drug Combination

General Information of Drug Combination (ID: DCZXQUU)

• Drug Combination Name: Melatonin + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  Melatonin (DMKWFBT): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 2
  Bliss Independence Score: 2
  Loewe Additivity Score: 11.58
  LHighest Single Agent (HSA) Score: 11.58

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Melatonin

Disease Entry	ICD 11	Status	REF
Depression	6A70-6A7Z	Approved	[2]
Insomnia	7A00-7A0Z	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2/3	[4]
Sleep disorder, initiating and maintaining sleep	N.A.	Investigative	[5]

Melatonin Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Quinone reductase 2 (NQO2)	TTJLP0R	NQO2_HUMAN	Inhibitor	[8]
Melatonin receptor type 1A (MTNR1A)	TT0WAIE	MTR1A_HUMAN	Binder	[9]

Melatonin Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[11]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[12]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[13]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[11]
Indoleamine 2,3-dioxygenase 1 (IDO1)	DE43MW5	I23O1_HUMAN	Metabolism	[14]
Hydroxyindole O-methyltransferase (ASMT)	DEHGR57	ASMT_HUMAN	Metabolism	[15]

Melatonin Interacts with 23 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Methylation	[11]
Alternative prion protein (PRNP)	OTE85L1Q	APRIO_HUMAN	Increases Expression	[16]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[17]
Mitofusin-2 (MFN2)	OTPYN8A3	MFN2_HUMAN	Increases Expression	[18]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Decreases Response To Substance	[19]
Osteocalcin (BGLAP)	OTK1YLWQ	OSTCN_HUMAN	Increases Expression	[20]
DNA excision repair protein ERCC-1 (ERCC1)	OTNPYQHI	ERCC1_HUMAN	Increases Expression	[21]
Fatty acid-binding protein, adipocyte (FABP4)	OT3DKFOU	FABP4_HUMAN	Decreases Expression	[20]
Aggrecan core protein (ACAN)	OTUOCW8K	PGCA_HUMAN	Increases Expression	[20]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Decreases Expression	[22]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[23]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Expression	[24]
Mitogen-activated protein kinase 9 (MAPK9)	OTCEVJ9E	MK09_HUMAN	Increases Expression	[24]
Mitogen-activated protein kinase 10 (MAPK10)	OTC46VX1	MK10_HUMAN	Increases Expression	[24]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Expression	[25]
Transcription factor A, mitochondrial (TFAM)	OTXXV5V7	TFAM_HUMAN	Increases Expression	[18]
POU domain, class 5, transcription factor 1 (POU5F1)	OTDHHN7O	PO5F1_HUMAN	Decreases Expression	[26]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)	OT4SO7J4	BNIP3_HUMAN	Increases Expression	[27]
Mitofusin-1 (MFN1)	OTCBXQZF	MFN1_HUMAN	Increases Expression	[18]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Phosphorylation	[28]
Serine/threonine-protein kinase PINK1, mitochondrial (PINK1)	OT50NR57	PINK1_HUMAN	Increases Expression	[27]
Diablo IAP-binding mitochondrial protein (DIABLO)	OTHJ9MCZ	DBLOH_HUMAN	Increases Expression	[17]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A)	OTHCDQ22	PRGC1_HUMAN	Increases Expression	[18]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[6]
Acute myeloid leukaemia	2A60	Approved	[7]
Adult acute monocytic leukemia	N.A.	Approved	[6]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[6]
Leukemia	N.A.	Approved	[6]

Idarubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Modulator	[30]

Idarubicin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[31]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[32]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[32]

Idarubicin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[33]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[33]

Idarubicin Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[34]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[29]

References

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• [2] Melatonin and its analogs in insomnia and depression. J Pineal Res. 2012 May;52(4):365-75.
• [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: 224).
• [4] COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 2020 Jun 1;250:117583.
• [5] Melatonin in sleep disorders. Neurologia (Engl Ed). 2022 Sep;37(7):575-585.
• [6] Idarubicin FDA Label
• [7] 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: 7083).
• [8] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [9] The human MT1 melatonin receptor stimulates cAMP production in the human neuroblastoma cell line SH-SY5Y cells via a calcium-calmodulin signal transduction pathway. J Neuroendocrinol. 2005 Mar;17(3):170-8.
• [10] Multiple P450 substrates in a single run: rapid and comprehensive in vitro interaction assay. Eur J Pharm Sci. 2005 Jan;24(1):123-32.
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• [12] New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I. Curr Drug Metab. 2009 Dec;10(10):1075-126.
• [13] The effect of CYP2C19 substrate on the metabolism of melatonin in the elderly: a randomized, double-blind, placebo-controlled study. Methods Find Exp Clin Pharmacol. 2006 Sep;28(7):447-50.
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• [21] Melatonin attenuates cisplatin-induced HepG2 cell death via the regulation of mTOR and ERCC1 expressions. World J Hepatol. 2014 Apr 27;6(4):230-42. doi: 10.4254/wjh.v6.i4.230.
• [22] Melatonin protects CD4+ T cells from activation-induced cell death by blocking NFAT-mediated CD95 ligand upregulation. J Immunol. 2010 Apr 1;184(7):3487-94. doi: 10.4049/jimmunol.0902961. Epub 2010 Feb 24.
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• [24] Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. J Pineal Res. 2008 Nov;45(4):532-40. doi: 10.1111/j.1600-079X.2008.00641.x.
• [25] Melatonin induces mitochondrial-mediated apoptosis in human myeloid HL-60 cells. J Pineal Res. 2009 May;46(4):392-400. doi: 10.1111/j.1600-079X.2009.00675.x. Epub 2009 Apr 9.
• [26] Melatonin decreases estrogen receptor binding to estrogen response elements sites on the OCT4 gene in human breast cancer stem cells. Genes Cancer. 2016 May;7(5-6):209-17. doi: 10.18632/genesandcancer.107.
• [27] Melatonin ameliorates acute lung injury caused by paraquat poisoning by promoting PINK1 and BNIP3 expression. Toxicology. 2023 May 15;490:153506. doi: 10.1016/j.tox.2023.153506. Epub 2023 Apr 5.
• [28] Melatonin prevents nitric oxide-induced apoptosis by increasing the interaction between 14-3-3beta and p-Bad in SK-N-MC cells. J Pineal Res. 2008 Jan;44(1):95-100. doi: 10.1111/j.1600-079X.2007.00494.x.
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• [32] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
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