Target Information
| Target General Information | Top | |||||
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| Target ID |
T99616
(Former ID: TTDR00585)
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| Target Name |
Trypanosoma Trypanothione reductase (Trypano TPR)
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| Synonyms |
TRYR; TPR; Parasite-specific trypanothione reductase; N(1),N(8)-bis(glutathionyl)spermidine reductase
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| Gene Name |
Trypano TPR
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Light sensitivity impairment [ICD-11: 9D45] | |||||
| 2 | Thrombocytopenia [ICD-11: 3B64] | |||||
| Function |
Trypanothione is the parasite analog of glutathione; this enzyme is the equivalent of glutathione reductase.
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| BioChemical Class |
Sulfur donor oxidoreductase
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| UniProt ID | ||||||
| EC Number |
EC 1.8.1.12
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| Sequence |
MSKIFDLVVIGAGSGGLEAGWNAATLYKKRVAVIDVQTHHGPPHYAALGGTCVNVGCVPK
KLMVTGAQYMDHLRESAGFGWEFDGSSVKANWKKLIAAKNEAVLDINKSYEGMFNDTEGL DFFLGWGSLESKNVVVVRETADPKSAVKERLQADHILLATGSWPQMPAIPGVEHCISSNE AFYLPEPPRRVLTVGGGFISVEFAGIFNAYKPPGGKVTLCYRNNLILRGFDETIREEVTK QLTANGIEIMTNENPAKVSLNTDGSKHVTFESGKTLDVDVVMMAIGRIPRTNDLQLGNVG VKLTPKGGVQVDEFSRTNVPNIYAIGDITDRLMLTPVAINEGAALVDTVFGNKPRKTDHT RVASAVFSIPPIGTCGLIEEVAAKEFEKVAVYMSSFTPLMHNISGSKYKKFVAKIVTNHS DGTVLGVHLLGDGAPEIIQAVGVCLRLNAKISDFYNTIGVHPTSAEELCSMRTPSYYYLK GEKMETLPESSL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Bivalirudin | Drug Info | Approved | Thrombocytopenia | [2], [3] | |
| 2 | Vitamin A | Drug Info | Approved | Night blindness | [4], [5] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 9 Inhibitor drugs | + | ||||
| 1 | Bivalirudin | Drug Info | [1] | |||
| 2 | 1-(2'-chlorophenyl)penta-1,4-dien-3-one | Drug Info | [7] | |||
| 3 | CEPHARANTINE | Drug Info | [8] | |||
| 4 | CONESSINE | Drug Info | [8] | |||
| 5 | Flavin-Adenine Dinucleotide | Drug Info | [9] | |||
| 6 | Maleic Acid | Drug Info | [10] | |||
| 7 | N-(5-chloro-2-(phenylthio)phenyl)butyramide | Drug Info | [11] | |||
| 8 | N1,N2-bis(dihydrocaffeoyl)spermine | Drug Info | [8] | |||
| 9 | Trypanothione | Drug Info | [9] | |||
| Binder | [+] 1 Binder drugs | + | ||||
| 1 | Vitamin A | Drug Info | [6] | |||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Flavin-Adenine Dinucleotide | Ligand Info | |||||
| Structure Description | Properties of Trypanothione Reductase From T. brucei | PDB:2WBA | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [12] |
| PDB Sequence |
SKAFDLVVIG
11 AGSGGLEAGW21 NAATLYGKRV31 AVVDVQTSHG41 PPFYAALGGT51 CVNVGCVPKK 61 LMVTGAQYMD71 HLRESAGFGW81 EFDGSSVKAN91 WKKLIAAKNE101 AVLDINKSYE 111 GMFNDTEGLD121 FFLGWGSLES131 KNVVVVRETA141 DPKSAVKERL151 QADHILLATG 161 SWPQMPAIPG171 IEHCISSNEA181 FYLPEPPRRV191 LTVGGGFISV201 EFAGIFNAYK 211 PPGGKVTLCY221 RNNLILRGFD231 ETIREEVTKQ241 LTANGIEIMT251 NENPAKVSLN 261 TDGSKHVTFE271 SGKTLDVDVV281 MMAIGRIPRT291 NDLQLGNVGV301 KLTPKGGVQV 311 DEFSRTNVPN321 IYAIGDITDR331 LMLTPVAINE341 GAALVDTVFG351 NKPRKTDHTR 361 VASAVFSIPP371 IGTCGLIEEV381 AAKEFEKVAV391 YMSSFTPLMH401 NISGSKYKKF 411 VAKIVTNHSD421 GTVLGVHLLG431 DGAPEIIQAV441 GVCLRLNAKI451 SDFYNTIGVH 461 PTSAEELCSM471 RTPSYYYVKG481 EKMEKLPDS
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ILE10
3.381
GLY11
3.149
ALA12
4.055
GLY13
3.379
SER14
3.311
GLY15
2.855
GLY16
3.993
VAL34
3.534
ASP35
2.743
VAL36
3.778
ALA46
3.630
ALA47
3.053
LEU48
4.818
GLY49
4.860
GLY50
3.443
THR51
2.592
CYS52
3.540
VAL55
3.825
GLY56
3.716
CYS57
3.297
LYS60
2.745
GLY125
3.758
TRP126
3.707
GLY127
2.832
ALA159
3.292
THR160
3.426
GLY161
3.424
SER162
4.398
SER178
4.079
PHE182
4.228
PHE198
3.787
ILE199
3.919
GLU202
4.496
PHE203
4.204
ARG287
3.455
ARG290
3.401
ASP293
4.225
LEU294
3.998
ILE325
4.121
GLY326
3.192
ASP327
2.864
ILE328
4.650
MET333
3.196
LEU334
3.216
THR335
2.987
PRO336
3.319
ALA338
3.891
PHE367
4.376
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| Ligand Name: NADPH | Ligand Info | |||||
| Structure Description | Properties of Trypanothione Reductase From T. brucei | PDB:2WBA | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [12] |
| PDB Sequence |
SKAFDLVVIG
11 AGSGGLEAGW21 NAATLYGKRV31 AVVDVQTSHG41 PPFYAALGGT51 CVNVGCVPKK 61 LMVTGAQYMD71 HLRESAGFGW81 EFDGSSVKAN91 WKKLIAAKNE101 AVLDINKSYE 111 GMFNDTEGLD121 FFLGWGSLES131 KNVVVVRETA141 DPKSAVKERL151 QADHILLATG 161 SWPQMPAIPG171 IEHCISSNEA181 FYLPEPPRRV191 LTVGGGFISV201 EFAGIFNAYK 211 PPGGKVTLCY221 RNNLILRGFD231 ETIREEVTKQ241 LTANGIEIMT251 NENPAKVSLN 261 TDGSKHVTFE271 SGKTLDVDVV281 MMAIGRIPRT291 NDLQLGNVGV301 KLTPKGGVQV 311 DEFSRTNVPN321 IYAIGDITDR331 LMLTPVAINE341 GAALVDTVFG351 NKPRKTDHTR 361 VASAVFSIPP371 IGTCGLIEEV381 AAKEFEKVAV391 YMSSFTPLMH401 NISGSKYKKF 411 VAKIVTNHSD421 GTVLGVHLLG431 DGAPEIIQAV441 GVCLRLNAKI451 SDFYNTIGVH 461 PTSAEELCSM471 RTPSYYYVKG481 EKMEKLPDS
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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 Similarity Proteins
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There is no similarity protein (E value < 0.005) for this target
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| 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 | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | 8-Methoxy-naphtho[2,3-b]thiophen-4,9-quinone, a non-competitive inhibitor of trypanothione reductase. Mem Inst Oswaldo Cruz. 2003 Jun;98(4):565-8. | |||||
| REF 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: 6470). | |||||
| REF 3 | Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. | |||||
| REF 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: 4053). | |||||
| REF 5 | Vitamins and cofactors: highlights of ESBOC 2009. Nat Chem Biol. 2009 Aug;5(8):530-3. | |||||
| REF 6 | Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40. | |||||
| REF 7 | Irreversible inactivation of trypanothione reductase by unsaturated Mannich bases: a divinyl ketone as key intermediate. J Med Chem. 2005 Nov 17;48(23):7400-10. | |||||
| REF 8 | The use of natural product scaffolds as leads in the search for trypanothione reductase inhibitors. Bioorg Med Chem. 2008 Jul 15;16(14):6689-95. | |||||
| REF 9 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 10 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 11 | Antitrypanosomal, antileishmanial, and antimalarial activities of quaternary arylalkylammonium 2-amino-4-chlorophenyl phenyl sulfides, a new class ... J Med Chem. 2005 Dec 15;48(25):8087-97. | |||||
| REF 12 | Comparative structural, kinetic and inhibitor studies of Trypanosoma brucei trypanothione reductase with T. cruzi. Mol Biochem Parasitol. 2010 Jan;169(1):12-9. | |||||
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