Details of the Drug Combination

General Information of Drug Combination (ID: DCFJTXD)

• Drug Combination Name: Tozadenant + Levodopa
• Indication: Parkinson's Disease; Status: Phase 1 [1]
• Component Drugs:
  Tozadenant (DMATC14): Small molecular drug
  Levodopa (DMN3E57): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tozadenant

Disease Entry	ICD 11	Status	REF
Parkinson disease	8A00.0	Phase 3	[2]

Tozadenant Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine A2a receptor (ADORA2A)	TTM2AOE	AA2AR_HUMAN	Antagonist	[5]

Indication(s) of Levodopa

Disease Entry	ICD 11	Status	REF
Parkinson disease	8A00.0	Approved	[3]
Parkinsonian disorder	N.A.	Approved	[4]
Postencephalitic Parkinson disease	N.A.	Approved	[4]

Levodopa Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Modulator	[3]

Levodopa Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]
L-type amino acid transporter 1 (SLC7A5)	DT48T0N	LAT1_HUMAN	Substrate	[8]

Levodopa Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[9]
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[10]
DOPA decarboxylase (DDC)	DETK9CN	DDC_HUMAN	Metabolism	[11]
Tyrosine decarboxylase (tdc)	DE3HL9N	TYRDC_ENTFA	Metabolism	[12]
Tyrosine decarboxylase (tdc)	DEX2ZLF	TYRDC_LACBR	Metabolism	[13]

Levodopa Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Aromatic-L-amino-acid decarboxylase (DDC)	OT0TSW09	DDC_HUMAN	Increases Response To Substance	[14]
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Increases Methylation	[15]
Rap guanine nucleotide exchange factor 3 (RAPGEF3)	OTMOW4Z4	RPGF3_HUMAN	Increases Expression	[16]
Vasopressin-neurophysin 2-copeptin (AVP)	OTAVZ76K	NEU2_HUMAN	Decreases Secretion	[17]
Thyrotropin subunit beta (TSHB)	OTFDI39D	TSHB_HUMAN	Decreases Expression	[18]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Decreases Expression	[18]
Somatotropin (GH1)	OT92RTRD	SOMA_HUMAN	Increases Expression	[18]
Dopamine beta-hydroxylase (DBH)	OTC6I2SP	DOPO_HUMAN	Decreases Activity	[19]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[16]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[16]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[20]
Mitogen-activated protein kinase kinase kinase 5 (MAP3K5)	OTQR6ENW	M3K5_HUMAN	Increases Activity	[20]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Affects Response To Substance	[21]
E3 ubiquitin-protein ligase parkin (PRKN)	OTJBN41W	PRKN_HUMAN	Increases ADR	[22]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases ADR	[22]
Opioid growth factor receptor (OGFR)	OTROS6RJ	OGFR_HUMAN	Increases ADR	[22]
Homer protein homolog 1 (HOMER1)	OTWFD3SI	HOME1_HUMAN	Affects Response To Substance	[23]

References

• [1] ClinicalTrials.gov (NCT01283594) Safety and Efficacy Study of SYN115 in Parkinson's Patients Using Levodopa to Treat End of Dose Wearing Off
• [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: 5611).
• [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: 3639).
• [4] Levodopa FDA Label
• [5] Tozadenant (SYN115) in patients with Parkinson's disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol. 2014 Aug;13(8):767-76.
• [6] Claudin-3 and claudin-4 regulate sensitivity to cisplatin by controlling expression of the copper and cisplatin influx transporter CTR1. Mol Pharmacol. 2013 Jan;83(1):85-94. doi: 10.1124/mol.112.079798. Epub 2012 Oct 10.
• [7] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [8] Modulation of LAT1 (SLC7A5) transporter activity and stability by membrane cholesterol. Sci Rep. 2017 Mar 8;7:43580.
• [9] Multiple cytochrome P450 enzymes responsible for the oxidative metabolism of the substituted (S)-3-phenylpiperidine, (S,S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, in human liver microsomes. Drug Metab Dispos. 2002 Dec;30(12):1372-7.
• [10] Reduced 3-O-methyl-dopa levels in OCD patients and their unaffected parents is associated with the low activity M158 COMT allele. Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):542-548.
• [11] Complexity of dopamine metabolism. Cell Commun Signal. 2013 May 17;11(1):34.
• [12] Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science. 2019 Jun 14;364(6445). pii: eaau6323.
• [13] Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson's disease. Nat Commun. 2019 Jan 18;10(1):310.
• [14] Focal striatal dopamine may potentiate dyskinesias in parkinsonian monkeys. Exp Neurol. 2006 Feb;197(2):363-72. doi: 10.1016/j.expneurol.2005.10.022. Epub 2005 Dec 9.
• [15] 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.
• [16] Multiple treatments with L-3,4-dihydroxyphenylalanine modulate dopamine biosynthesis and neurotoxicity through the protein kinase A-transient extracellular signal-regulated kinase and exchange protein activation by cyclic AMP-sustained extracellular signal-regulated kinase signaling pathways. J Neurosci Res. 2014 Dec;92(12):1746-56. doi: 10.1002/jnr.23450. Epub 2014 Jul 12.
• [17] Blood pressure and vasopressin in progressive autonomic failure. Response to postural stimulation, L-dopa and naloxone. Brain. 1983 Jun;106 (Pt 2):503-11. doi: 10.1093/brain/106.2.503.
• [18] Effects of terguride on anterior pituitary function in parkinsonian patients treated with L-dopa: a double-blind study versus placebo. Clin Neuropharmacol. 1996 Feb;19(1):72-80. doi: 10.1097/00002826-199619010-00006.
• [19] Plasma dopamine beta hydroxylase (D.B.H.) activity in Parkinsonian patients under L-dopa, and 2-bromo-alpha-ergocriptine loading. J Neural Transm. 1979;46(1):71-8. doi: 10.1007/BF01243430.
• [20] Levodopa activates apoptosis signaling kinase 1 (ASK1) and promotes apoptosis in a neuronal model: implications for the treatment of Parkinson's disease. Chem Res Toxicol. 2011 Oct 17;24(10):1644-52. doi: 10.1021/tx200082h. Epub 2011 Aug 22.
• [21] Effects of wild-type and mutated copper/zinc superoxide dismutase on neuronal survival and L-DOPA-induced toxicity in postnatal midbrain culture. J Neurochem. 1997 Jul;69(1):21-33. doi: 10.1046/j.1471-4159.1997.69010021.x.
• [22] 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.
• [23] Association of common genetic variants of HOMER1 gene with levodopa adverse effects in Parkinson's disease patients. Pharmacogenomics J. 2014 Jun;14(3):289-94. doi: 10.1038/tpj.2013.37. Epub 2013 Oct 15.