Target Information
| Target General Information | Top | |||||
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| Target ID |
T59554
(Former ID: TTDI01430)
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| Target Name |
Mycobacterium Decaprenylphosphoryl-beta-D-ribose oxidase (McyB dprE1)
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| Synonyms |
FAD-dependent decaprenylphosphoryl-beta-D-ribofuranose 2-oxidase; Decaprenylphosphoryl-beta-D-ribose oxidase; Decaprenylphosphoryl-beta-D-ribose 2-epimerase flavoprotein subunit; Decaprenylphosphoryl-beta-D-ribofuranose 2'-oxidase; Decaprenylphosphoryl-beta-D-ribofuranose 2'-epimerase subunit DprE1; Decaprenylphospho-beta-D-ribofuranose 2-dehydrogenase; Decaprenyl-phosphoribose 2'-epimerase subunit 1
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| Gene Name |
McyB dprE1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | HIV-infected patients with tuberculosis [ICD-11: 1B10-1B14] | |||||
| 2 | Mycobacterium infection [ICD-11: 1B10-1B21] | |||||
| Function |
Component of the DprE1-DprE2 complex that catalyzes the 2-step epimerization of decaprenyl-phospho-ribose (DPR) to decaprenyl-phospho-arabinose (DPA), a key precursor that serves as the arabinose donor required for the synthesis of cell-wall arabinans. DprE1 catalyzes the first step of epimerization, namely FAD-dependent oxidation of the C2' hydroxyl of DPR to yield the keto intermediate decaprenyl-phospho-2'-keto-D-arabinose (DPX). The intermediate DPX is then transferred to DprE2 subunit of the epimerase complex, most probably through a 'substrate channel' at the interface of DprE1-DprE2 complex. Can also use farnesyl-phosphoryl-beta-D-ribofuranose (FPR) as substrate in vitro. Appears to be essential for the growth and survival of M.tuberculosis.
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| UniProt ID | ||||||
| EC Number |
EC 1.1.98.3
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| Sequence |
MLSVGATTTATRLTGWGRTAPSVANVLRTPDAEMIVKAVARVAESGGGRGAIARGLGRSY
GDNAQNGGGLVIDMTPLNTIHSIDADTKLVDIDAGVNLDQLMKAALPFGLWVPVLPGTRQ VTVGGAIACDIHGKNHHSAGSFGNHVRSMDLLTADGEIRHLTPTGEDAELFWATVGGNGL TGIIMRATIEMTPTSTAYFIADGDVTASLDETIALHSDGSEARYTYSSAWFDAISAPPKL GRAAVSRGRLATVEQLPAKLRSEPLKFDAPQLLTLPDVFPNGLANKYTFGPIGELWYRKS GTYRGKVQNLTQFYHPLDMFGEWNRAYGPAGFLQYQFVIPTEAVDEFKKIIGVIQASGHY SFLNVFKLFGPRNQAPLSFPIPGWNICVDFPIKDGLGKFVSELDRRVLEFGGRLYTAKDS RTTAETFHAMYPRVDEWISVRRKVDPLRVFASDMARRLELL 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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| Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
| 1 | BTZ-043 | Drug Info | Phase 2 | Tuberculosis | [2] | |
| 2 | TBA-7371 | Drug Info | Phase 2 | Tuberculosis | [3] | |
| 3 | OPC-167832 | Drug Info | Phase 1/2 | Tuberculosis | [4] | |
| 4 | Macozinone | Drug Info | Phase 1 | Mycobacterium infection | [5] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | TBA-7371 | Drug Info | [7] | |||
| 2 | OPC-167832 | Drug Info | [8] | |||
| 3 | Macozinone | Drug Info | [9] | |||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Flavin-Adenine Dinucleotide | Ligand Info | |||||
| Structure Description | Crystal structure of M. tuberculosis DprE1 in complex with the non-covalent inhibitor QN118 | PDB:4P8N | ||||
| Method | X-ray diffraction | Resolution | 1.79 Å | Mutation | No | [10] |
| PDB Sequence |
VGATTTATRL
13 TGWGRTAPSV23 ANVLRTPDAE33 MIVKAVARVA43 ESGGGRGAIA53 RGLGRSYGDN 63 AQNGGGLVID73 MTPLNTIHSI83 DADTKLVDID93 AGVNLDQLMK103 AALPFGLWVP 113 VLPGTRQVTV123 GGAIACDIHG133 KNHHSAGSFG143 NHVRSMDLLT153 ADGEIRHLTP 163 TGEDAELFWA173 TVGGNGLTGI183 IMRATIEMTP193 TSTAYFIADG203 DVTASLDETI 213 ALHSDGSEAR223 YTYSSAWFDA233 ISAPPKLGRA243 AVSRGRLATV253 EQLPAKLRSE 263 PLKFDAPQLL273 TLPDVFPNGL283 ANKYTFGPIG293 ELWYRKSGTY303 RGKVQNLTQF 313 YHPLDMFGEW323 NRAGFLQYQF337 VIPTEAVDEF347 KKIIGVIQAS357 GHYSFLNVFK 367 LFGPRNQAPL377 SFPIPGWNIC387 VDFPIKDGLG397 KFVSELDRRV407 LEFGGRLYTA 417 KDSRTTAETF427 HAMYPRVDEW437 ISVRRKVDPL447 RVFASDMARR457 LELL |
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TRP16
3.535
ILE52
3.360
ALA53
2.650
ARG54
3.783
GLY55
2.711
LEU56
3.157
GLY57
2.970
ARG58
2.734
SER59
2.671
TYR60
3.612
ASN63
3.156
ALA64
3.587
MET74
3.585
ALA94
3.498
LEU115
4.971
PRO116
3.430
GLY117
2.931
THR118
3.431
GLN120
4.272
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: 8-(Oxidanylamino)-2-piperidin-1-yl-6-(trifluoromethyl)-1,3-benzothiazin-4-one | Ligand Info | |||||
| Structure Description | Mycobacterium tuberculosis DprE1 in complex with CMP2 | PDB:6HFV | ||||
| Method | X-ray diffraction | Resolution | 2.05 Å | Mutation | No | [11] |
| PDB Sequence |
TTTATRLTGW
16 GRTAPSVANV26 LRTPDAEMIV36 KAVARVAESG48 RGAIARGLGR58 SYGDNAQNGG 68 GLVIDMTPLN78 TIHSIDADTK88 LVDIDAGVNL98 DQLMKAALPF108 GLWVPVLPGT 118 RQVTVGGAIA128 CDIHGKNHHS138 AGSFGNHVRS148 MDLLTADGEI158 RHLTPTGEDA 168 ELFWATVGGN178 GLTGIIMRAT188 IEMTPTSTAY198 FIADGDVTAS208 LDETIALHSD 218 GSEARYTYSS228 AWFDAISAPP238 KLGRAAVSRG248 RLATVEQLPA258 KLRSEPLKFD 268 ANKYTFGPIG293 ELWYRKSGTY303 RGKVQNLTQF313 YHPLDMGFLQ334 YQFVIPTEAV 344 DEFKKIIGVI354 QASGHYSFLN364 VFKLFGPRNQ374 APLSFPIPGW384 NICVDFPIKD 394 GLGKFVSELD404 RRVLEFGGRL414 YTAKDSRTTA424 ETFHAMYPRV434 DEWISVRRKV 444 DPLRVFASDM454 ARRLELL
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TYR60
4.666
PRO116
4.851
GLY117
3.471
HIS132
3.676
GLY133
3.081
LYS134
2.524
SER227
4.676
SER228
3.773
TRP230
4.090
TYR314
4.491
LEU317
3.410
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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 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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| References | Top | |||||
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| REF 1 | Decaprenyl-phosphoryl-ribose 2'-epimerase (DprE1): challenging target for antitubercular drug discovery. Chem Cent J. 2018 Jun 23;12(1):72. | |||||
| REF 2 | ClinicalTrials.gov (NCT04044001) A Prospective Phase Ib/IIa, Active-controlled, Randomized, Open-label Study to Evaluate the Safety, Tolerability, Extended Early Bactericidal Activity and Pharmacokinetics of Multiple Oral Doses of BTZ-043 Tablets in Subjects With Newly Diagnosed, Uncomplicated, Smear-positive, Drug-susceptible Pulmonary Tuberculosis. U.S.National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT03199339) A Phase 1 Study to Evaluate Safety, Tolerability, PK, and PK Interactions of TBA-7371. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT03678688) A Phase 1/2 Trial of Multiple Oral Doses of OPC-167832 for Uncomplicated Pulmonary Tuberculosis. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT04150224) Safety, Tolerability, Pharmacokinetics and Food Effects Study of PBTZ169. U.S. National Institutes of Health. | |||||
| REF 6 | Clinical pipeline report, company report or official report of TB | |||||
| REF 7 | Clinical pipeline report, company report or official report of TB Alliance. | |||||
| REF 8 | OPC-167832, a Novel Carbostyril Derivative with Potent Antituberculosis Activity as a DprE1 Inhibitor. Antimicrob Agents Chemother. 2020 May 21;64(6):e02020-19. | |||||
| REF 9 | Spirocyclic and Bicyclic 8-Nitrobenzothiazinones for Tuberculosis with Improved Physicochemical and Pharmacokinetic Properties. ACS Med Chem Lett. 2019 Feb 23;10(3):348-351. | |||||
| REF 10 | 2-Carboxyquinoxalines kill mycobacterium tuberculosis through noncovalent inhibition of DprE1. ACS Chem Biol. 2015 Mar 20;10(3):705-14. | |||||
| REF 11 | Novel insight into the reaction of nitro, nitroso and hydroxylamino benzothiazinones and of benzoxacinones with Mycobacterium tuberculosis DprE1. Sci Rep. 2018 Sep 7;8(1):13473. | |||||
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