Target Information
| Target General Information | Top | |||||
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| Target ID |
T44818
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| Target Name |
Tryptophan 2,3-dioxygenase (TDO)
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| Synonyms |
Tryptophanase; Tryptophan pyrrolase; Tryptophan oxygenase; Tryptamin 2,3-dioxygenase; TRPO; TO
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| Gene Name |
TDO2
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Catalyzes the oxidative cleavage of the indole moiety. Heme-dependent dioxygenase that catalyzes the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring and converts L-tryptophan to N-formyl-L-kynurenine.
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| BioChemical Class |
Oxygenase
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| UniProt ID | ||||||
| EC Number |
EC 1.13.11.11
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| Sequence |
MSGCPFLGNNFGYTFKKLPVEGSEEDKSQTGVNRASKGGLIYGNYLHLEKVLNAQELQSE
TKGNKIHDEHLFIITHQAYELWFKQILWELDSVREIFQNGHVRDERNMLKVVSRMHRVSV ILKLLVQQFSILETMTALDFNDFREYLSPASGFQSLQFRLLENKIGVLQNMRVPYNRRHY RDNFKGEENELLLKSEQEKTLLELVEAWLERTPGLEPHGFNFWGKLEKNITRGLEEEFIR IQAKEESEEKEEQVAEFQKQKEVLLSLFDEKRHEHLLSKGERRLSYRALQGALMIYFYRE EPRFQVPFQLLTSLMDIDSLMTKWRYNHVCMVHRMLGSKAGTGGSSGYHYLRSTVSDRYK VFVDLFNLSTYLIPRHWIPKMNPTIHKFLYTAEYCDSSYFSSDESD Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T40DE5 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | DN1406131 | Drug Info | Phase 1 | Solid tumour/cancer | [2] | |
| 2 | HTI-1090 | Drug Info | Phase 1 | Solid tumour/cancer | [3] | |
| Preclinical Drug(s) | [+] 5 Preclinical Drugs | + | ||||
| 1 | 4-(4-fluoropyrazol-1-yl)-1,2-oxazol-5-amine | Drug Info | Preclinical | Solid tumour/cancer | [4] | |
| 2 | 680C91 | Drug Info | Preclinical | Solid tumour/cancer | [4] | |
| 3 | EPL-1410 | Drug Info | Preclinical | Solid tumour/cancer | [4] | |
| 4 | LM10 | Drug Info | Preclinical | Solid tumour/cancer | [4] | |
| 5 | RG70099 | Drug Info | Preclinical | Solid tumour/cancer | [4] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 17 Inhibitor drugs | + | ||||
| 1 | DN1406131 | Drug Info | [2] | |||
| 2 | HTI-1090 | Drug Info | [5] | |||
| 3 | 2,3-diamino-benzo[b]thiophene derivative 1 | Drug Info | [6] | |||
| 4 | 2,3-diamino-benzo[b]thiophene derivative 2 | Drug Info | [6] | |||
| 5 | 2,3-diamino-benzo[b]thiophene derivative 3 | Drug Info | [6] | |||
| 6 | 2,3-diamino-benzo[b]thiophene derivative 4 | Drug Info | [6] | |||
| 7 | 2,3-diamino-benzo[b]thiophene derivative 5 | Drug Info | [6] | |||
| 8 | 2,3-diamino-benzo[b]thiophene derivative 6 | Drug Info | [6] | |||
| 9 | 2,3-diamino-benzo[b]thiophene derivative 7 | Drug Info | [6] | |||
| 10 | 2,3-diamino-benzo[b]thiophene derivative 8 | Drug Info | [6] | |||
| 11 | PMID27172114-Compound-30 | Drug Info | [6] | |||
| 12 | PMID29473428-Compound-76 | Drug Info | [1] | |||
| 13 | 4-(4-fluoropyrazol-1-yl)-1,2-oxazol-5-amine | Drug Info | [4] | |||
| 14 | 680C91 | Drug Info | [7] | |||
| 15 | EPL-1410 | Drug Info | [4] | |||
| 16 | LM10 | Drug Info | [8] | |||
| 17 | RG70099 | Drug Info | [4] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: NOX-200 | Ligand Info | |||||
| Structure Description | Crystal Structure of human Tryptophan 2,3-dioxygenase in complex with PF-06840003 in Active Site | PDB:6PYZ | ||||
| Method | X-ray diffraction | Resolution | 2.02 Å | Mutation | No | [9] |
| PDB Sequence |
GLIYGNYLHL
48 EKVLNAQELQ58 SETKGNKIHD68 EHLFIITHQA78 YELWFKQILW88 ELDSVREIFQ 98 NGHVRDERNM108 LKVVSRMHRV118 SVILKLLVQQ128 FSILETMTAL138 DFNDFREYLS 148 PASGFQSLQF158 RLLENKIGVL168 QNMRVPYNRR178 HYRDNFKGEE188 NELLLKSEQE 198 KTLLELVEAW208 LERTPGLEPH218 GFNFWGKLEK228 NITRGLEEEF238 IRIQAKEESE 248 EKEEQVAEFQ258 KQKEVLLSLF268 DEKRHEHLLS278 KGERRLSYRA288 LQGALMIYFY 298 REEPRFQVPF308 QLLTSLMDID318 SLMTKWRYNH328 VCMVHRMLGS338 KAGTGGSSGY 348 HYLRSTVSDR358 YKVFVDLFNL368 STYLIPRHWI378 PKMNPTIHKF388 LEH |
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| Ligand Name: 1-(6-chloro-1H-indazol-4-yl)cyclohexan-1-ol | Ligand Info | |||||
| Structure Description | Crystal Structure of human TDO inhibitor complex | PDB:6A4I | ||||
| Method | X-ray diffraction | Resolution | 2.65 Å | Mutation | No | [10] |
| PDB Sequence |
LIYGNYLHLE
49 KVLNAQELQS59 ETKGNKIHDE69 HLFIITHQAY79 ELWFKQILWE89 LDSVREIFQN 99 GHVRDERNML109 KVVSRMHRVS119 VILKLLVQQF129 SILETMTALD139 FNDFREYLSP 149 ASGFQSLQFR159 LLENKIGVLQ169 NMNFKGEENE190 LLLKSEQEKT200 LLELVEAWLE 210 RTPGLEPHGF220 NFWGKLEKNI230 TRGLEEEFIR240 IQAEEKEEQV254 AEFQKQKEVL 264 LSLFDEKRHE274 HLLSKGERRL284 SYRALQGALM294 IYFYREEPRF304 QVPFQLLTSL 314 MDIDSLMTKW324 RYNHVCMVHR334 MLGSGSSGYH349 YLRSTVSDRY359 KVFVDLFNLS 369 TYLIPRHWIP379 KM
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Tryptophan metabolism | hsa00380 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Degree | 5 | Degree centrality | 5.37E-04 | Betweenness centrality | 3.09E-04 |
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| Closeness centrality | 1.41E-01 | Radiality | 1.16E+01 | Clustering coefficient | 4.00E-01 |
| Neighborhood connectivity | 5.20E+00 | Topological coefficient | 3.85E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Tryptophan metabolism | |||||
| 2 | Metabolic pathways | |||||
| References | Top | |||||
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| REF 1 | A patent review of IDO1 inhibitors for cancer.Expert Opin Ther Pat. 2018 Apr;28(4):317-330. | |||||
| REF 2 | ClinicalTrials.gov (NCT03641794) Indoleamine 2,3-Dioxygenase (IDO) Inhibitor in Healthy Volunteers. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT03208959) A Trial of HTI-1090 in Subjects With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 4 | Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov. 2019 May;18(5):379-401. | |||||
| REF 5 | Discovery of cyanopyridine scaffold as novel indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors through virtual screening and preliminary hit optimisation. J Enzyme Inhib Med Chem. 2019 Dec;34(1):250-263. | |||||
| REF 6 | Inhibitors of the kynurenine pathway as neurotherapeutics: a patent review (2012-2015).Expert Opin Ther Pat. 2016 Jul;26(7):815-32. | |||||
| REF 7 | Effects of IDO1 and TDO2 inhibition on cognitive deficits and anxiety following LPS-induced neuroinflammation. Acta Neuropsychiatr. 2020 Feb;32(1):43-53. | |||||
| REF 8 | The autoimmune response elicited by mouse hepatitis virus (MHV-A59) infection is modulated by liver tryptophan-2,3-dioxygenase (TDO). Immunol Lett. 2020 Jan;217:25-30. | |||||
| REF 9 | Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase. J Am Chem Soc. 2019 Nov 27;141(47):18771-18779. | |||||
| REF 10 | Crystal Structure of human TDO inhibitor complex | |||||
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