Details of the Drug Combination

General Information of Drug Combination (ID: DCUNON9)

• Drug Combination Name: Amodiaquine + Novobiocin
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Amodiaquine (DME4RA8): Small molecular drug
  Novobiocin (DMRFWGK): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 16.83
  Bliss Independence Score: 16.83
  Loewe Additivity Score: 32.05
  LHighest Single Agent (HSA) Score: 32.05

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Amodiaquine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[2]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[3]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[3]

Amodiaquine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histamine N-methyltransferase (HNMT)	TT2B6EV	HNMT_HUMAN	Inhibitor	[5]

Amodiaquine Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[6]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[7]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[6]
Glutathione S-transferase mu-4 (GSTM4)	DERQ52Z	GSTM4_HUMAN	Metabolism	[8]
Cytochrome P450 102A1 (cyp102)	DE4OGUF	CPXB_BACMB	Metabolism	[9]

Amodiaquine Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[10]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[11]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Affects Phosphorylation	[12]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[11]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Affects Expression	[12]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Decreases Expression	[11]
Transcription factor E2F1 (E2F1)	OTLKYBBC	E2F1_HUMAN	Affects Expression	[12]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[11]

Indication(s) of Novobiocin

Disease Entry	ICD 11	Status	REF
Bacterial infection	1A00-1C4Z	Approved	[4]

Novobiocin 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	Inhibitor	[13]

Novobiocin Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cadherin-2 (CDH2)	OTH0Y56P	CADH2_HUMAN	Decreases Expression	[14]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Activity	[15]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Drug information of Amodiaquine, 2008. eduDrugs.
• [3] Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014 Aug;58(8):4885-93.
• [4] How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73.
• [5] Effect of amodiaquine, a histamine N-methyltransferase inhibitor, on, Propionibacterium acnes and lipopolysaccharide-induced hepatitis in mice. Eur J Pharmacol. 2007 Mar 8;558(1-3):179-84.
• [6] Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J Pharmacol Exp Ther. 2002 Feb;300(2):399-407.
• [7] Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa. Clin Pharmacol Ther. 2007 Aug;82(2):197-203.
• [8] Human glutathione S-transferases- and NAD(P)H:quinone oxidoreductase 1-catalyzed inactivation of reactive quinoneimines of amodiaquine and N-desethylamodiaquine: possible implications for susceptibility to amodiaquine-induced liver toxicity. Toxicol Lett. 2017 Jun 5;275:83-91.
• [9] The bacterial P450 BM3: a prototype for a biocatalyst with human P450 activities. Trends Biotechnol. 2007 Jul;25(7):289-98.
• [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] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [12] The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death. Autophagy. 2013 Dec;9(12):2087-102. doi: 10.4161/auto.26506. Epub 2013 Oct 8.
• [13] Transcriptional responses of Bacillus subtillis and thuringiensis to antibiotics and anti-tumour drugs. Int J Mol Med. 2009 Jan;23(1):33-9.
• [14] Novobiocin is a novel inducer of CD38 on cells of the myelomonocytic lineage. Biochim Biophys Acta. 2002 Jan 30;1542(1-3):32-40. doi: 10.1016/s0167-4889(01)00163-x.
• [15] 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.