Details of the Drug Combination

General Information of Drug Combination (ID: DCKHO60)

• Drug Combination Name: Dopamine + Nitrosoglutathione
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Dopamine (DMPGUCF): Small molecular drug
  Nitrosoglutathione (DMZ9WI4): N.A.
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 15.24
  Bliss Independence Score: 15.24
  Loewe Additivity Score: 27.31
  LHighest Single Agent (HSA) Score: 27.32

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Dopamine

Disease Entry	ICD 11	Status	REF
Acromegaly	5A60.0	Approved	[2]
Carcinoid syndrome	5B10	Approved	[2]
Parkinson disease	8A00.0	Approved	[3]
Parkinsonian disorder	N.A.	Approved	[2]
Postencephalitic Parkinson disease	N.A.	Approved	[2]
Hypotension	BA20-BA21	Phase 1	[3]

Dopamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Agonist	[7]

Dopamine Interacts with 6 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[8]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[9]
Vesicular amine transporter 2 (SLC18A2)	DTT7VPB	VMAT2_HUMAN	Substrate	[10]
Vesicular amine transporter 1 (SLC18A1)	DTM953D	VMAT1_HUMAN	Substrate	[10]
Synaptic vesicle glycoprotein 2C (SLC22B3)	DT7A9GF	SV2C_HUMAN	Substrate	[11]
Sodium-dependent dopamine transporter (SLC6A3)	DT3BA8L	SC6A3_HUMAN	Substrate	[12]

Dopamine Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[13]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[14]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[14]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[14]
Catechol O-methyltransferase (COMT)	DEV3T4A	COMT_HUMAN	Metabolism	[15]
Monoamine oxidase type B (MAO-B)	DET2NXO	AOFB_HUMAN	Metabolism	[16]
Sulfotransferase 1B1 (SULT1B1)	DED5UR3	ST1B1_HUMAN	Metabolism	[17]
Dopamine dehydroxylase (dadH)	DEL0D64	DADH_EGGLN	Metabolism	[18]

Dopamine Interacts with 41 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Increases Activity	[19]
Glial fibrillary acidic protein (GFAP)	OTQ01ZAS	GFAP_HUMAN	Increases ADR	[20]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)	OT4SO7J4	BNIP3_HUMAN	Increases Expression	[21]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[21]
POTE ankyrin domain family member F (POTEF)	OTV3WXYE	POTEF_HUMAN	Increases Expression	[4]
Citrate synthase, mitochondrial (CS)	OTYLYXMO	CISY_HUMAN	Increases Expression	[4]
ATP synthase subunit d, mitochondrial (ATP5PD)	OTAJDLE2	ATP5H_HUMAN	Increases Expression	[4]
Prelamin-A/C (LMNA)	OT3SG7ZR	LMNA_HUMAN	Increases Expression	[4]
Fructose-bisphosphate aldolase A (ALDOA)	OTWRFTIB	ALDOA_HUMAN	Increases Expression	[4]
ADP/ATP translocase 2 (SLC25A5)	OT1XIBMN	ADT2_HUMAN	Increases Expression	[4]
Heat shock protein HSP 90-beta (HSP90AB1)	OTR69EG7	HS90B_HUMAN	Increases Expression	[4]
Small ribosomal subunit protein uS2 (RPSA)	OTJZHEGT	RSSA_HUMAN	Increases Expression	[4]
POTE ankyrin domain family member I (POTEI)	OTST4AVP	POTEI_HUMAN	Decreases Expression	[4]
ADP/ATP translocase 3 (SLC25A6)	OT9KAJP7	ADT3_HUMAN	Increases Expression	[4]
Annexin A3 (ANXA3)	OTDD8OI7	ANXA3_HUMAN	Increases Expression	[4]
Histone H1.5 (H1-5)	OTAN7RD9	H15_HUMAN	Increases Expression	[4]
Heat shock 70 kDa protein 6 (HSPA6)	OTH4S7WB	HSP76_HUMAN	Increases Expression	[4]
Cofilin-1 (CFL1)	OTT6D5MH	COF1_HUMAN	Increases Expression	[4]
Thioredoxin-dependent peroxide reductase, mitochondrial (PRDX3)	OTLB2WEU	PRDX3_HUMAN	Increases Expression	[4]
Protein disulfide-isomerase A3 (PDIA3)	OTHPQ0Q3	PDIA3_HUMAN	Decreases Expression	[4]
Serine hydroxymethyltransferase, mitochondrial (SHMT2)	OT5NCAZN	GLYM_HUMAN	Increases Expression	[4]
Stress-70 protein, mitochondrial (HSPA9)	OT4TMVS9	GRP75_HUMAN	Increases Expression	[4]
Actin, cytoplasmic 1 (ACTB)	OT1MCP2F	ACTB_HUMAN	Affects Expression	[4]
Small ribosomal subunit protein RACK1 (RACK1)	OTZBCQ1U	RACK1_HUMAN	Increases Expression	[4]
Elongation factor 1-alpha 1 (EEF1A1)	OT00THXS	EF1A1_HUMAN	Increases Expression	[4]
Single-stranded DNA-binding protein, mitochondrial (SSBP1)	OTH2PZWH	SSBP_HUMAN	Increases Expression	[4]
Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP)	OTPYQX3K	C1QBP_HUMAN	Increases Expression	[4]
Beta-actin-like protein 2 (ACTBL2)	OTD6B81U	ACTBL_HUMAN	Decreases Expression	[4]
5'-3' exonuclease PLD3 (PLD3)	OTL07SP2	PLD3_HUMAN	Affects Expression	[4]
Septin-9 (SEPTIN9)	OT1VMRFQ	SEPT9_HUMAN	Decreases Expression	[4]
RuvB-like 1 (RUVBL1)	OTWV19L7	RUVB1_HUMAN	Increases Expression	[4]
E3 ubiquitin-protein ligase parkin (PRKN)	OTJBN41W	PRKN_HUMAN	Increases Expression	[22]
Brain mitochondrial carrier protein 1 (SLC25A14)	OT1ZQSKS	UCP5_HUMAN	Increases Expression	[23]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Phosphorylation	[24]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[24]
D(1A) dopamine receptor (DRD1)	OTLZPBT7	DRD1_HUMAN	Increases Activity	[25]
Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1)	OTGYVSGU	PIMT_HUMAN	Decreases Expression	[26]
Alpha-synuclein (SNCA)	OTPWC1MR	SYUA_HUMAN	Increases Response To Substance	[27]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[28]
Secretin (SCT)	OTV3MLOO	SECR_HUMAN	Increases Metabolism	[29]
Equilibrative nucleoside transporter 4 (SLC29A4)	OTWTZXMX	S29A4_HUMAN	Increases Uptake	[28]

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	[30]

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	[31]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Decreases Secretion	[32]
Interleukin-12 subunit beta (IL12B)	OT0JF8A3	IL12B_HUMAN	Decreases Expression	[32]
Transcription factor Sp3 (SP3)	OTYDQZ1T	SP3_HUMAN	Decreases Activity	[33]
Carbonyl reductase 1 (CBR1)	OTQ3A541	CBR1_HUMAN	Increases Reduction	[34]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Response To Substance	[35]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Dopamine FDA Label
• [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: 940).
• [4] Mitochondrial proteomics investigation of a cellular model of impaired dopamine homeostasis, an early step in Parkinson's disease pathogenesis. Mol Biosyst. 2014 Jun;10(6):1332-44.
• [5] Vitamin D signaling and the differentiation of developing dopamine systems. Neuroscience. 2016 Oct 1;333:193-203. doi: 10.1016/j.neuroscience.2016.07.020. Epub 2016 Jul 20.
• [6] Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N=1198) using genome-wide search. Mol Psychiatry. 2011 Sep;16(9):927-37, 881. doi: 10.1038/mp.2011.32. Epub 2011 Apr 19.
• [7] The Detection of Dopamine Gene Receptors (DRD1-DRD5) Expression on Human Peripheral Blood Lymphocytes by Real Time PCR. Iran J Allergy Asthma Immunol. 2004 Dec;3(4):169-74.
• [8] Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006 Jun;50(8):941-52.
• [9] Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences. Drug Metab Pharmacokinet. 2008;23(4):243-53.
• [10] SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol Aspects Med. 2013 Apr-Jun;34(2-3):360-72.
• [11] Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease. Proc Natl Acad Sci U S A. 2017 Mar 14;114(11):E2253-E2262.
• [12] Characterization of VNTRs Within the Entire Region of SLC6A3 and Its Association with Hypertension. DNA Cell Biol. 2017 Mar;36(3):227-236.
• [13] Modulation of CYP1A2 enzyme activity by indoleamines: inhibition by serotonin and tryptamine. Pharmacogenetics. 1998 Jun;8(3):251-8.
• [14] Pharmacogenetics of schizophrenia. Am J Med Genet. 2000 Spring;97(1):98-106.
• [15] Association between polymorphisms in catechol-O-methyltransferase (COMT) and cocaine-induced paranoia in European-American and African-American populations. Am J Med Genet B Neuropsychiatr Genet. 2011 Sep;156B(6):651-60.
• [16] Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury. Biochim Biophys Acta. 2011 Jul;1813(7):1323-32.
• [17] Molecular cloning, expression, and functional characterization of novel mouse sulfotransferases. Biochem Biophys Res Commun. 1998 Jun 29;247(3):681-6.
• [18] Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science. 2019 Jun 14;364(6445). pii: eaau6323.
• [19] Functional characterization of N-octyl 4-methylamphetamine variants and related bivalent compounds at the dopamine and serotonin transporters using Ca(2+) channels as sensors. Toxicol Appl Pharmacol. 2021 May 15;419:115513. doi: 10.1016/j.taap.2021.115513. Epub 2021 Mar 27.
• [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.
• [21] Effects of dopamine on LC3-II activation as a marker of autophagy in a neuroblastoma cell model. Neurotoxicology. 2009 Jul;30(4):658-65. doi: 10.1016/j.neuro.2009.04.007. Epub 2009 May 4.
• [22] Induction of parkin expression in the presence of oxidative stress. Eur J Neurosci. 2006 Sep;24(5):1366-72. doi: 10.1111/j.1460-9568.2006.04998.x.
• [23] Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity. Free Radic Biol Med. 2010 Sep 15;49(6):1023-35. doi: 10.1016/j.freeradbiomed.2010.06.017. Epub 2010 Jun 19.
• [24] Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis. Hum Mol Genet. 2004 Aug 15;13(16):1745-54. doi: 10.1093/hmg/ddh180. Epub 2004 Jun 15.
• [25] Characterizing fucoxanthin as a selective dopamine D(3)/D(4) receptor agonist: Relevance to Parkinson's disease. Chem Biol Interact. 2019 Sep 1;310:108757. doi: 10.1016/j.cbi.2019.108757. Epub 2019 Jul 16.
• [26] Dopamine down-regulation of protein L-isoaspartyl methyltransferase is dependent on reactive oxygen species in SH-SY5Y cells. Neuroscience. 2014 May 16;267:263-76. doi: 10.1016/j.neuroscience.2014.03.001. Epub 2014 Mar 12.
• [27] G209A mutant alpha synuclein expression specifically enhances dopamine induced oxidative damage. Neurochem Int. 2004 Oct;45(5):669-76. doi: 10.1016/j.neuint.2004.03.029.
• [28] Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther. 2010 Dec;335(3):743-53. doi: 10.1124/jpet.110.170142. Epub 2010 Sep 21.
• [29] Administration of secretin for autism alters dopamine metabolism in the central nervous system. Brain Dev. 2006 Mar;28(2):99-103. doi: 10.1016/j.braindev.2005.05.005. Epub 2005 Sep 15.
• [30] Nitrosative stress response in Vibrio cholerae: role of S-nitrosoglutathione reductase. Appl Biochem Biotechnol. 2017 Jul;182(3):871-884.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] Studies on reduction of S-nitrosoglutathione by human carbonyl reductases 1 and 3. Chem Biol Interact. 2011 May 30;191(1-3):95-103.
• [35] 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.