Details of the Drug Combination

General Information of Drug Combination (ID: DCS4F0L)

• Drug Combination Name: Dopamine + Pramipexole
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Dopamine (DMPGUCF): Small molecular drug
  Pramipexole (DMNMW9R): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 57.04
  Bliss Independence Score: 57.04
  Loewe Additivity Score: 69.99
  LHighest Single Agent (HSA) Score: 69.99

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	[8]

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	[9]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[10]
Vesicular amine transporter 2 (SLC18A2)	DTT7VPB	VMAT2_HUMAN	Substrate	[11]
Vesicular amine transporter 1 (SLC18A1)	DTM953D	VMAT1_HUMAN	Substrate	[11]
Synaptic vesicle glycoprotein 2C (SLC22B3)	DT7A9GF	SV2C_HUMAN	Substrate	[12]
Sodium-dependent dopamine transporter (SLC6A3)	DT3BA8L	SC6A3_HUMAN	Substrate	[13]

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	[14]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[15]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[15]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[15]
Catechol O-methyltransferase (COMT)	DEV3T4A	COMT_HUMAN	Metabolism	[16]
Monoamine oxidase type B (MAO-B)	DET2NXO	AOFB_HUMAN	Metabolism	[17]
Sulfotransferase 1B1 (SULT1B1)	DED5UR3	ST1B1_HUMAN	Metabolism	[18]
Dopamine dehydroxylase (dadH)	DEL0D64	DADH_EGGLN	Metabolism	[19]

Dopamine Interacts with 76 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases Abundance	[20]
Amine oxidase B (MAOB)	OTTDFM1O	AOFB_HUMAN	Decreases Amination	[21]
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Increases Methylation	[22]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Increases Activity	[23]
Synaptic vesicular amine transporter (SLC18A2)	OTUOMMM6	VMAT2_HUMAN	Decreases Activity	[24]
Glial fibrillary acidic protein (GFAP)	OTQ01ZAS	GFAP_HUMAN	Increases ADR	[25]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[26]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)	OT4SO7J4	BNIP3_HUMAN	Increases Expression	[26]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[26]
Glutathione S-transferase A1 (GSTA1)	OTA7K5XA	GSTA1_HUMAN	Decreases Activity	[27]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Activity	[27]
Glutathione S-transferase Mu 1 (GSTM1)	OTSBF2MO	GSTM1_HUMAN	Decreases Activity	[27]
Methionine synthase (MTR)	OTF2K2TA	METH_HUMAN	Increases Activity	[28]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[29]
POTE ankyrin domain family member F (POTEF)	OTV3WXYE	POTEF_HUMAN	Increases Expression	[5]
Citrate synthase, mitochondrial (CS)	OTYLYXMO	CISY_HUMAN	Increases Expression	[5]
ATP synthase subunit d, mitochondrial (ATP5PD)	OTAJDLE2	ATP5H_HUMAN	Increases Expression	[5]
Prelamin-A/C (LMNA)	OT3SG7ZR	LMNA_HUMAN	Increases Expression	[5]
Fructose-bisphosphate aldolase A (ALDOA)	OTWRFTIB	ALDOA_HUMAN	Increases Expression	[5]
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)	OTBPMIMW	G3P_HUMAN	Increases Expression	[5]
ADP/ATP translocase 2 (SLC25A5)	OT1XIBMN	ADT2_HUMAN	Increases Expression	[5]
Cathepsin D (CTSD)	OTQZ36F3	CATD_HUMAN	Increases Expression	[5]
Heat shock protein HSP 90-beta (HSP90AB1)	OTR69EG7	HS90B_HUMAN	Increases Expression	[5]
Small ribosomal subunit protein uS2 (RPSA)	OTJZHEGT	RSSA_HUMAN	Increases Expression	[5]
POTE ankyrin domain family member I (POTEI)	OTST4AVP	POTEI_HUMAN	Decreases Expression	[5]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[5]
ADP/ATP translocase 3 (SLC25A6)	OT9KAJP7	ADT3_HUMAN	Increases Expression	[5]
Annexin A3 (ANXA3)	OTDD8OI7	ANXA3_HUMAN	Increases Expression	[5]
Pyruvate kinase PKM (PKM)	OTLHHMC2	KPYM_HUMAN	Increases Expression	[5]
Endoplasmin (HSP90B1)	OT02XLBR	ENPL_HUMAN	Increases Expression	[5]
Histone H1.5 (H1-5)	OTAN7RD9	H15_HUMAN	Increases Expression	[5]
Heat shock 70 kDa protein 6 (HSPA6)	OTH4S7WB	HSP76_HUMAN	Increases Expression	[5]
Nucleolin (NCL)	OTBXPKMP	NUCL_HUMAN	Increases Expression	[5]
Cofilin-1 (CFL1)	OTT6D5MH	COF1_HUMAN	Increases Expression	[5]
Myristoylated alanine-rich C-kinase substrate (MARCKS)	OT7N056G	MARCS_HUMAN	Increases Expression	[5]
Thioredoxin-dependent peroxide reductase, mitochondrial (PRDX3)	OTLB2WEU	PRDX3_HUMAN	Increases Expression	[5]
Protein disulfide-isomerase A3 (PDIA3)	OTHPQ0Q3	PDIA3_HUMAN	Decreases Expression	[5]
Serine hydroxymethyltransferase, mitochondrial (SHMT2)	OT5NCAZN	GLYM_HUMAN	Increases Expression	[5]
Prohibitin 1 (PHB1)	OTZNXYS2	PHB1_HUMAN	Increases Expression	[5]
Stress-70 protein, mitochondrial (HSPA9)	OT4TMVS9	GRP75_HUMAN	Increases Expression	[5]
Actin, cytoplasmic 1 (ACTB)	OT1MCP2F	ACTB_HUMAN	Affects Expression	[5]
Small ribosomal subunit protein RACK1 (RACK1)	OTZBCQ1U	RACK1_HUMAN	Increases Expression	[5]
Elongation factor 1-alpha 1 (EEF1A1)	OT00THXS	EF1A1_HUMAN	Increases Expression	[5]
Single-stranded DNA-binding protein, mitochondrial (SSBP1)	OTH2PZWH	SSBP_HUMAN	Increases Expression	[5]
Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP)	OTPYQX3K	C1QBP_HUMAN	Increases Expression	[5]
Beta-actin-like protein 2 (ACTBL2)	OTD6B81U	ACTBL_HUMAN	Decreases Expression	[5]
5'-3' exonuclease PLD3 (PLD3)	OTL07SP2	PLD3_HUMAN	Affects Expression	[5]
Septin-9 (SEPTIN9)	OT1VMRFQ	SEPT9_HUMAN	Decreases Expression	[5]
RuvB-like 1 (RUVBL1)	OTWV19L7	RUVB1_HUMAN	Increases Expression	[5]
E3 ubiquitin-protein ligase parkin (PRKN)	OTJBN41W	PRKN_HUMAN	Increases Expression	[30]
Brain mitochondrial carrier protein 1 (SLC25A14)	OT1ZQSKS	UCP5_HUMAN	Increases Expression	[31]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Affects Binding	[32]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Decreases Expression	[33]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Increases Expression	[34]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Phosphorylation	[35]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[35]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[36]
D(1A) dopamine receptor (DRD1)	OTLZPBT7	DRD1_HUMAN	Increases Activity	[37]
Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1)	OTGYVSGU	PIMT_HUMAN	Decreases Expression	[38]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[26]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[26]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[26]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[26]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Decreases Expression	[26]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[26]
Sulfotransferase 1A1 (SULT1A1)	OT0K7JIE	ST1A1_HUMAN	Increases Metabolism	[39]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Uptake	[40]
Tyrosine 3-monooxygenase (TH)	OT6ZORKP	TY3H_HUMAN	Increases Chemical Synthesis	[41]
Amine oxidase A (MAOA)	OT8NIWMQ	AOFA_HUMAN	Decreases Amination	[21]
Sulfotransferase 1A3 (SULT1A4)	OTHJ8WWV	ST1A3_HUMAN	Increases Metabolism	[39]
Alpha-synuclein (SNCA)	OTPWC1MR	SYUA_HUMAN	Increases Response To Substance	[42]
Neuron-specific vesicular protein calcyon (CALY)	OTQ7EMPU	CALY_HUMAN	Decreases Secretion	[43]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[44]
Secretin (SCT)	OTV3MLOO	SECR_HUMAN	Increases Metabolism	[45]
Equilibrative nucleoside transporter 4 (SLC29A4)	OTWTZXMX	S29A4_HUMAN	Increases Uptake	[44]
GDP-mannose 4,6 dehydratase (GMDS)	OTWV79YD	GMDS_HUMAN	Increases ADR	[7]

Indication(s) of Pramipexole

Disease Entry	ICD 11	Status	REF
Parkinson disease	8A00.0	Approved	[4]

Pramipexole Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D3 receptor (D3R)	TT4C8EA	DRD3_HUMAN	Modulator	[46]
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Modulator	[46]

Pramipexole Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[47]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[48]

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] 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] 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: 953).
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006 Jun;50(8):941-52.
• [10] Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences. Drug Metab Pharmacokinet. 2008;23(4):243-53.
• [11] SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol Aspects Med. 2013 Apr-Jun;34(2-3):360-72.
• [12] 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.
• [13] Characterization of VNTRs Within the Entire Region of SLC6A3 and Its Association with Hypertension. DNA Cell Biol. 2017 Mar;36(3):227-236.
• [14] Modulation of CYP1A2 enzyme activity by indoleamines: inhibition by serotonin and tryptamine. Pharmacogenetics. 1998 Jun;8(3):251-8.
• [15] Pharmacogenetics of schizophrenia. Am J Med Genet. 2000 Spring;97(1):98-106.
• [16] 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.
• [17] Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury. Biochim Biophys Acta. 2011 Jul;1813(7):1323-32.
• [18] Molecular cloning, expression, and functional characterization of novel mouse sulfotransferases. Biochem Biophys Res Commun. 1998 Jun 29;247(3):681-6.
• [19] Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science. 2019 Jun 14;364(6445). pii: eaau6323.
• [20] Effect of penicillin-based antibiotics, amoxicillin, ampicillin, and piperacillin, on drug-metabolizing activities of human hepatic cytochromes P450. J Toxicol Sci. 2016 Feb;41(1):143-6.
• [21] Inhibition potential of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolites on the in vitro monoamine oxidase (MAO)-catalyzed deamination of the neurotransmitters serotonin and dopamine. Toxicol Lett. 2016 Jan 22;243:48-55.
• [22] Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase. Mol Pharmacol. 2001 Feb;59(2):393-402. doi: 10.1124/mol.59.2.393.
• [23] 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.
• [24] The effect of rare human sequence variants on the function of vesicular monoamine transporter 2. Pharmacogenetics. 2004 Sep;14(9):587-94. doi: 10.1097/00008571-200409000-00003.
• [25] 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.
• [26] 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.
• [27] Inhibition of human glutathione S-transferases by dopamine, alpha-methyldopa and their 5-S-glutathionyl conjugates. Chem Biol Interact. 1994 Jan;90(1):87-99.
• [28] Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. Mol Psychiatry. 2004 Apr;9(4):358-70.
• [29] Functional expression and comparative characterization of nine murine cytochromes P450 by fluorescent inhibition screening. Drug Metab Dispos. 2008 Jul;36(7):1322-31.
• [30] 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.
• [31] 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.
• [32] Ligand binding and aggregation of pathogenic SOD1. Nat Commun. 2013;4:1758. doi: 10.1038/ncomms2750.
• [33] Dose-dependent separation of dopaminergic and adrenergic effects of epinine in healthy volunteers. Naunyn Schmiedebergs Arch Pharmacol. 1995 Oct;352(4):429-37. doi: 10.1007/BF00172781.
• [34] Effect of drugs interacting with the dopaminergic receptors on glucose levels and insulin release in healthy and type 2 diabetic subjects. Am J Ther. 2008 Jul-Aug;15(4):397-402. doi: 10.1097/MJT.0b013e318160c353.
• [35] 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.
• [36] Resveratrol protects SH-SY5Y neuroblastoma cells from apoptosis induced by dopamine. Exp Mol Med. 2007 Jun 30;39(3):376-84. doi: 10.1038/emm.2007.42.
• [37] 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.
• [38] 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.
• [39] Sulfation of environmental estrogen-like chemicals by human cytosolic sulfotransferases. Biochem Biophys Res Commun. 2000 Jan 7;267(1):80-4. doi: 10.1006/bbrc.1999.1935.
• [40] Role of tumor necrosis factor-alpha in methamphetamine-induced drug dependence and neurotoxicity. J Neurosci. 2004 Mar 3;24(9):2212-25. doi: 10.1523/JNEUROSCI.4847-03.2004.
• [41] Expression of tyrosine hydroxylase increases the resistance of human neuroblastoma cells to oxidative insults. Toxicol Sci. 2010 Jan;113(1):150-7. doi: 10.1093/toxsci/kfp245. Epub 2009 Oct 8.
• [42] 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.
• [43] Increased arterial pressure in mice with overexpression of the ADHD candidate gene calcyon in forebrain. PLoS One. 2019 Feb 12;14(2):e0211903. doi: 10.1371/journal.pone.0211903. eCollection 2019.
• [44] 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.
• [45] 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.
• [46] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [47] Uptake of pramipexole by human organic cation transporters. Mol Pharm. 2010 Aug 2;7(4):1342-7.
• [48] OCT1 polymorphism is associated with response and survival time in anti-Parkinsonian drug users. Neurogenetics. 2011 Feb;12(1):79-82.