Target Information
| Target General Information | Top | |||||
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| Target ID |
T84581
(Former ID: TTDS00276)
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| Target Name |
Cytoplasmic thioredoxin reductase (TXNRD1)
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| Synonyms |
Thioredoxin reductase TR1; Thioredoxin reductase 1, cytoplasmic; KM-102-derived reductase-like factor; KDRF; Gene associated with retinoic and interferon-induced mortality 12 protein; Gene associated with retinoic and IFN-induced mortality 12 protein; GRIM12; GRIM-12
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| Gene Name |
TXNRD1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Isoform 1 may possess glutaredoxin activity as well as thioredoxin reductase activity and induces actin and tubulin polymerization, leading to formation of cell membrane protrusions. Isoform 4 enhances the transcriptional activity of estrogen receptors alpha and beta while isoform 5 enhances the transcriptional activity of the beta receptor only. Isoform 5 also mediates cell death induced by a combination of interferon-beta and retinoic acid.
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| BioChemical Class |
Sulfur donor oxidoreductase
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| UniProt ID | ||||||
| EC Number |
EC 1.8.1.9
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| Sequence |
MGCAEGKAVAAAAPTELQTKGKNGDGRRRSAKDHHPGKTLPENPAGFTSTATADSRALLQ
AYIDGHSVVIFSRSTCTRCTEVKKLFKSLCVPYFVLELDQTEDGRALEGTLSELAAETDL PVVFVKQRKIGGHGPTLKAYQEGRLQKLLKMNGPEDLPKSYDYDLIIIGGGSGGLAAAKE AAQYGKKVMVLDFVTPTPLGTRWGLGGTCVNVGCIPKKLMHQAALLGQALQDSRNYGWKV EETVKHDWDRMIEAVQNHIGSLNWGYRVALREKKVVYENAYGQFIGPHRIKATNNKGKEK IYSAERFLIATGERPRYLGIPGDKEYCISSDDLFSLPYCPGKTLVVGASYVALECAGFLA GIGLDVTVMVRSILLRGFDQDMANKIGEHMEEHGIKFIRQFVPIKVEQIEAGTPGRLRVV AQSTNSEEIIEGEYNTVMLAIGRDACTRKIGLETVGVKINEKTGKIPVTDEEQTNVPYIY AIGDILEDKVELTPVAIQAGRLLAQRLYAGSTVKCDYENVPTTVFTPLEYGACGLSEEKA VEKFGEENIEVYHSYFWPLEWTIPSRDNNKCYAKIICNTKDNERVVGFHVLGPNAGEVTQ GFAAALKCGLTKKQLDSTIGIHPVCAEVFTTLSVTKRSGASILQAGCUG Click to Show/Hide
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| HIT2.0 ID | T77W6N | |||||
| Drugs and Modes of Action | Top | |||||
|---|---|---|---|---|---|---|
| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Fotemustine | Drug Info | Approved | Solid tumour/cancer | [2] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Spermidine | Drug Info | Phase 3 | Plaque psoriasis | [3], [4] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 64 Inhibitor drugs | + | ||||
| 1 | Fotemustine | Drug Info | [1] | |||
| 2 | Spermidine | Drug Info | [1] | |||
| 3 | 4-aryl quinol derivative 1 | Drug Info | [5] | |||
| 4 | 4-aryl quinol derivative 2 | Drug Info | [5] | |||
| 5 | 4-aryl quinol derivative 3 | Drug Info | [5] | |||
| 6 | 4-aryl quinol derivative 4 | Drug Info | [5] | |||
| 7 | 4-aryl quinol derivative 5 | Drug Info | [5] | |||
| 8 | 4-aryl quinol derivative 7 | Drug Info | [5] | |||
| 9 | Acyl oxymethyl acrylamide ester derivative 1 | Drug Info | [5] | |||
| 10 | Acyl oxymethyl acrylamide ester derivative 2 | Drug Info | [5] | |||
| 11 | Benzisoselenazolone difluorocytidine derivative 1 | Drug Info | [5] | |||
| 12 | Binuclear gold(I) compound 1 | Drug Info | [5] | |||
| 13 | Binuclear gold(I) compound 2 | Drug Info | [5] | |||
| 14 | Binuclear gold(I) compound 3 | Drug Info | [5] | |||
| 15 | Bis-sulfonamide derivative 1 | Drug Info | [5] | |||
| 16 | Bis-sulfonamide derivative 2 | Drug Info | [5] | |||
| 17 | Disulfide compound 1 | Drug Info | [5] | |||
| 18 | Disulfide compound 2 | Drug Info | [5] | |||
| 19 | Golden phosphorous acetyletic compound 1 | Drug Info | [5] | |||
| 20 | Golden phosphorous acetyletic compound 2 | Drug Info | [5] | |||
| 21 | Golden phosphorous acetyletic compound 3 | Drug Info | [5] | |||
| 22 | Metal complex derivative 1 | Drug Info | [5] | |||
| 23 | Metal complex derivative 2 | Drug Info | [5] | |||
| 24 | Metal complex derivative 3 | Drug Info | [5] | |||
| 25 | Palmarumycin derivative 1 | Drug Info | [5] | |||
| 26 | Palmarumycin derivative 2 | Drug Info | [5] | |||
| 27 | Palmarumycin derivative 3 | Drug Info | [5] | |||
| 28 | Palmarumycin derivative 4 | Drug Info | [5] | |||
| 29 | PMID27977313-Compound-17 | Drug Info | [5] | |||
| 30 | PMID27977313-Compound-18 | Drug Info | [5] | |||
| 31 | PMID27977313-Compound-19 | Drug Info | [5] | |||
| 32 | PMID27977313-Compound-27 | Drug Info | [5] | |||
| 33 | PMID27977313-Compound-28 | Drug Info | [5] | |||
| 34 | PMID27977313-Compound-29 | Drug Info | [5] | |||
| 35 | PMID27977313-Compound-30 | Drug Info | [5] | |||
| 36 | PMID27977313-Compound-31 | Drug Info | [5] | |||
| 37 | PMID27977313-Compound-32 | Drug Info | [5] | |||
| 38 | PMID27977313-Compound-39 | Drug Info | [5] | |||
| 39 | PMID27977313-Compound-42 | Drug Info | [5] | |||
| 40 | PMID27977313-Compound-43 | Drug Info | [5] | |||
| 41 | PMID27977313-Compound-44 | Drug Info | [5] | |||
| 42 | PMID27977313-Compound-45 | Drug Info | [5] | |||
| 43 | PMID27977313-Compound-46 | Drug Info | [5] | |||
| 44 | PMID27977313-Compound-47 | Drug Info | [5] | |||
| 45 | PMID27977313-Compound-48 | Drug Info | [5] | |||
| 46 | PMID27977313-Compound-5 | Drug Info | [5] | |||
| 47 | PMID27977313-Compound-6 | Drug Info | [5] | |||
| 48 | PMID27977313-Compound-7 | Drug Info | [5] | |||
| 49 | PMID27977313-Compound-8 | Drug Info | [5] | |||
| 50 | PMID27977313-Compound-Figure4b | Drug Info | [5] | |||
| 51 | PMID27977313-Compound-Figure6C | Drug Info | [5] | |||
| 52 | Terpyridineplatinum(II) complexe 1 | Drug Info | [5] | |||
| 53 | Terpyridineplatinum(II) complexe 2 | Drug Info | [5] | |||
| 54 | Terpyridineplatinum(II) complexe 3 | Drug Info | [5] | |||
| 55 | Terpyridineplatinum(II) complexe 4 | Drug Info | [5] | |||
| 56 | Terpyridineplatinum(II) complexe 5 | Drug Info | [5] | |||
| 57 | Triazole gold complexe 1 | Drug Info | [5] | |||
| 58 | Triazole gold complexe 2 | Drug Info | [5] | |||
| 59 | Triazole gold complexe 3 | Drug Info | [5] | |||
| 60 | 3-formyl-4-phenyl-1,2,5-oxadiazole 2-oxide | Drug Info | [6] | |||
| 61 | 4,6-dinitrobenzo[c][1,2,5]thiadiazole | Drug Info | [7] | |||
| 62 | 5,8-Dihydroxy-1,4-naphthoquinone | Drug Info | [8] | |||
| 63 | Bis(2,4-dinitrophenyl)sulfane | Drug Info | [7] | |||
| 64 | Flavin-Adenine Dinucleotide | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
|---|---|---|---|---|---|---|
| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Flavin-Adenine Dinucleotide | Ligand Info | |||||
| Structure Description | Crystal structure of the human thioredoxin reductase-thioredoxin complex | PDB:3QFA | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | Yes | [9] |
| PDB Sequence |
DLPKSYDYDL
15 IIIGGGSGGL25 AAAKEAAQYG35 KKVMVLDFVT45 PTPLGTRWGL55 GGTCVNVGCI 65 PKKLMHQAAL75 LGQALQDSRN85 YGWKVEETVK95 HDWDRMIEAV105 QNHIGSLNWG 115 YRVALREKKV125 VYENAYGQFI135 GPHRIKATNN145 KGKEKIYSAE155 RFLIATGERP 165 RYLGIPGDKE175 YCISSDDLFS185 LPYCPGKTLV195 VGASYVALEC205 AGFLAGIGLD 215 VTVMVRSILL225 RGFDQDMANK235 IGEHMEEHGI245 KFIRQFVPIK255 VEQIEAGTPG 265 RLRVVAQSTN275 SEEIIEGEYN285 TVMLAIGRDA295 CTRKIGLETV305 GVKINEKTGK 315 IPVTDEEQTN325 VPYIYAIGDI335 LEDKVELTPV345 AIQAGRLLAQ355 RLYAGSTVKC 365 DYENVPTTVF375 TPLEYGACGL385 SEEKAVEKFG395 EENIEVYHSY405 FWPLEWTIPS 415 RDNNKCYAKI425 ICNTKDNERV435 VGFHVLGPNA445 GEVTQGFAAA455 LKCGLTKKQL 465 DSTIGIHPVC475 AEVFTTLSVT485 KRSGASILQA495 GSCG
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ILE18
3.490
GLY19
3.043
GLY20
3.725
GLY21
3.281
SER22
3.253
GLY23
2.858
GLY24
4.143
LEU41
3.392
ASP42
2.579
PHE43
2.662
VAL44
3.854
THR45
4.945
GLY56
4.616
GLY57
3.726
THR58
2.824
CYS59
3.185
VAL62
3.537
GLY63
3.452
CYS64
3.314
LYS67
2.723
ALA130
3.665
TYR131
3.048
GLY132
2.804
ALA160
3.356
THR161
3.105
GLY162
3.436
GLU163
4.187
SER180
3.548
PHE184
3.778
TYR200
3.328
VAL201
3.635
GLU204
4.579
ARG293
3.229
CYS296
4.391
ILE300
3.395
ILE332
4.151
GLY333
2.983
ASP334
2.766
ILE335
4.782
GLU341
3.200
LEU342
3.424
THR343
3.199
PRO344
3.330
ALA346
3.754
THR373
4.967
PHE375
3.994
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: NADP+ | Ligand Info | |||||
| Structure Description | Crystal structure of NADP(H):human thioredoxin reductase I | PDB:2ZZC | ||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [10] |
| PDB Sequence |
SYDYDLIIIG
19 GGSGGLAAAK29 EAAQYGKKVM39 VLDFVTPTPL49 GTRWGLGGTC59 VNVGCIPKKL 69 MHQAALLGQA79 LQDSRNYGWK89 VEETVKHDWD99 RMIEAVQNHI109 GSLNWGYRVA 119 LREKKVVYEN129 AYGQFIGPHR139 IKATNNKGKE149 KIYSAERFLI159 ATGERPRYLG 169 IPGDKEYCIS179 SDDLFSLPYC189 PGKTLVVGAS199 YVALECAGFL209 AGIGLDVTVM 219 VRSILLRGFD229 QDMANKIGEH239 MEEHGIKFIR249 QFVPIKVEQI259 EAGTPGRLRV 269 VAQSTNSEEI279 IEGEYNTVML289 AIGRDACTRK299 IGLETVGVKI309 NEKTGKIPVT 319 DEEQTNVPYI329 YAIGDILEDK339 VELTPVAIQA349 GRLLAQRLYA359 GSTVKCDYEN 369 VPTTVFTPLE379 YGACGLSEEK389 AVEKFGEENI399 EVYHSYFWPL409 EWTIPSRDNN 419 KCYAKIICNT429 KDNERVVGFH439 VLGPNAGEVT449 QGFAAALKCG459 LTKKQLDSTI 469 GIHPVCAEVF479 TTLSVTKRSG489 ASILQ
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LYS67
3.668
ARG166
4.473
LEU168
2.792
VAL196
3.783
GLY197
3.926
ALA198
3.014
SER199
3.185
TYR200
3.127
VAL201
3.362
ALA202
4.567
GLU204
3.001
ARG221
3.053
SER222
2.791
ILE223
4.002
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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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| Selenocompound metabolism | hsa00450 | Affiliated Target |
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| Class: Metabolism => Metabolism of other amino acids | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 6.67E-04 |
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| Closeness centrality | 1.84E-01 | Radiality | 1.31E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.00E+01 | Topological coefficient | 5.00E-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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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 5 | Thioredoxin reductase inhibitors: a patent review.Expert Opin Ther Pat. 2017 May;27(5):547-556. | |||||
| REF 6 | Structure mechanism insights and the role of nitric oxide donation guide the development of oxadiazole-2-oxides as therapeutic agents against schis... J Med Chem. 2009 Oct 22;52(20):6474-83. | |||||
| REF 7 | Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents. Bioorg Med Chem Lett. 2006 Apr 15;16(8):2283-92. | |||||
| REF 8 | Novel molecular targets for antimalarial chemotherapy. Int J Antimicrob Agents. 2007 Jul;30(1):4-10. | |||||
| REF 9 | Crystal structure of the human thioredoxin reductase-thioredoxin complex. Nat Commun. 2011 Jul 12;2:383. | |||||
| REF 10 | Terpyridine-platinum(II) complexes are effective inhibitors of mammalian topoisomerases and human thioredoxin reductase 1. J Inorg Biochem. 2009 Jul;103(7):1082-92. | |||||
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