Details of the Drug Combination

General Information of Drug Combination (ID: DCS7RD0)

• Drug Combination Name: Entacapone + Methylene blue
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Entacapone (DMLBVKQ): Small molecular drug
  Methylene blue (DMJAPE7): N.A.
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 2.33
  Bliss Independence Score: 2.33
  Loewe Additivity Score: 3.12
  LHighest Single Agent (HSA) Score: 3.13

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Entacapone

Disease Entry	ICD 11	Status	REF
Parkinson disease	8A00.0	Approved	[2]

Entacapone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Catechol-O-methyl-transferase (COMT)	TTKWFB8	COMT_HUMAN	Inhibitor	[7]

Entacapone Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[8]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[9]

Entacapone Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[6]

Entacapone Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM)	OTR1XD9B	GPAT1_HUMAN	Decreases Expression	[10]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[11]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[11]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[11]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Decreases Expression	[11]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[11]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[11]
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Decreases Activity	[12]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[11]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Decreases Expression	[11]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Decreases Expression	[11]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[11]

Indication(s) of Methylene blue

Disease Entry	ICD 11	Status	REF
Acquired methemoglobinemia	3A93	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]

Methylene blue Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Monoamine oxidase (MAO)	TT32XQJ	NOUNIPROTAC	.	[13]
Guanylate cyclase (GC)	TT6HPVC	NOUNIPROTAC	Inhibitor	[14]

Methylene blue Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Amine oxidase B (MAOB)	OTTDFM1O	AOFB_HUMAN	Decreases Activity	[15]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[16]
Microtubule-associated protein tau (MAPT)	OTMTP2Z7	TAU_HUMAN	Increases Expression	[17]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Increases Activity	[18]
Acetylcholinesterase (ACHE)	OT2H8HG6	ACES_HUMAN	Decreases Activity	[19]
6-phosphogluconate dehydrogenase, decarboxylating (PGD)	OTVG296F	6PGD_HUMAN	Increases Activity	[18]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases ADR	[20]

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: 6647).
• [3] Recombinant Plasmodium falciparum glutathione reductase is inhibited by the antimalarial dye methylene blue. FEBS Lett. 1998 Feb 6;422(3):311-4.
• [4] ClinicalTrials.gov (NCT04370288) Clinical Application of Methylene Blue for Treatment of Covid-19 Patients. U.S. National Institutes of Health.
• [5] Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism. Neurology. 2005 Dec 13;65(11):1820-2. doi: 10.1212/01.wnl.0000187066.81162.70.
• [6] Kinetic characterization of the 1A subfamily of recombinant human UDP-glucuronosyltransferases. Drug Metab Dispos. 2005 Jul;33(7):1017-26.
• [7] Entacapone: a catechol-O-methyltransferase inhibitor for the adjunctive treatment of Parkinson's disease. Clin Ther. 2001 Jun;23(6):802-32; discussion 771.
• [8] Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors. Drug Metab Dispos. 2017 Dec;45(12):1282-1291.
• [9] Organic Anion Transporter 2-Mediated Hepatic Uptake Contributes to the Clearance of High-Permeability-Low-Molecular-Weight Acid and Zwitterion Drugs: Evaluation Using 25 Drugs. J Pharmacol Exp Ther. 2018 Nov;367(2):322-334.
• [10] Effect of the Catechol-O-Methyltransferase Inhibitors Tolcapone and Entacapone on Fatty Acid Metabolism in HepaRG Cells. Toxicol Sci. 2018 Aug 1;164(2):477-488.
• [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] Beneficial effects of natural phenolics on levodopa methylation and oxidative neurodegeneration. Brain Res. 2013 Feb 25;1497:1-14. doi: 10.1016/j.brainres.2012.11.043. Epub 2012 Dec 1.
• [13] Photoluminescence of CdTe nanocrystals modulated by methylene blue and DNA. A label-free luminescent signaling nanohybrid platform. Phys Chem Chem Phys. 2009 Jul 7;11(25):5062-9.
• [14] Curcumin ameliorates high glucose-induced acute vascular endothelial dysfunction in rat thoracic aorta. Clin Exp Pharmacol Physiol. 2009 Dec;36(12):1177-82.
• [15] Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors. Food Chem Toxicol. 2011 Aug;49(8):1773-81.
• [16] Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation. Arch Toxicol. 2022 Jul;96(7):1975-1987. doi: 10.1007/s00204-022-03291-5. Epub 2022 Apr 18.
• [17] Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression. Mol Neurodegener. 2006 Jul 26;1:6. doi: 10.1186/1750-1326-1-6.
• [18] Defenses against oxidation in human erythrocytes: role of glutathione reductase in the activation of glucose decarboxylation by hemolytic drugs. J Lab Clin Med. 1991 Apr;117(4):325-31.
• [19] Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition. Environ Health Perspect. 2021 Apr;129(4):47008. doi: 10.1289/EHP6993. Epub 2021 Apr 12.
• [20] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.