Target Information
| Target General Information | Top | |||||
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| Target ID |
T89360
(Former ID: TTDS00063)
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| Target Name |
Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2)
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| Synonyms |
IMPDH-II; IMPDH 2; IMPD2; IMPD 2; IMP dehydrogenase 2
Click to Show/Hide
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| Gene Name |
IMPDH2
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Transplant rejection [ICD-11: NE84] | |||||
| Function |
Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism. It may also have a role in the development of malignancy and the growth progression of some tumors. Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth.
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| BioChemical Class |
CH-OH donor oxidoreductase
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| UniProt ID | ||||||
| EC Number |
EC 1.1.1.205
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| Sequence |
MADYLISGGTSYVPDDGLTAQQLFNCGDGLTYNDFLILPGYIDFTADQVDLTSALTKKIT
LKTPLVSSPMDTVTEAGMAIAMALTGGIGFIHHNCTPEFQANEVRKVKKYEQGFITDPVV LSPKDRVRDVFEAKARHGFCGIPITDTGRMGSRLVGIISSRDIDFLKEEEHDCFLEEIMT KREDLVVAPAGITLKEANEILQRSKKGKLPIVNEDDELVAIIARTDLKKNRDYPLASKDA KKQLLCGAAIGTHEDDKYRLDLLAQAGVDVVVLDSSQGNSIFQINMIKYIKDKYPNLQVI GGNVVTAAQAKNLIDAGVDALRVGMGSGSICITQEVLACGRPQATAVYKVSEYARRFGVP VIADGGIQNVGHIAKALALGASTVMMGSLLAATTEAPGEYFFSDGIRLKKYRGMGSLDAM DKHLSSQNRYFSEADKIKVAQGVSGAVQDKGSIHKFVPYLIAGIQHSCQDIGAKSLTQVR AMMYSGELKFEKRTSSAQVEGGVHSLHSYEKRLF Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T68B5V | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Mycophenolate mofetil | Drug Info | Approved | Organ transplant rejection | [2], [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 33 Inhibitor drugs | + | ||||
| 1 | Mycophenolate mofetil | Drug Info | [1] | |||
| 2 | Urea and carbamate bioisostere derivative 1 | Drug Info | [4] | |||
| 3 | 1-(3-cyano-1-methyl-1H-indol-6-yl)-3-phenylurea | Drug Info | [5] | |||
| 4 | 1-methoxy-3-(3-(pyridin-4-yl)-1H-indol-6-yl)urea | Drug Info | [5] | |||
| 5 | 1-methyl-1H-indole-3-carbaldehyde | Drug Info | [6] | |||
| 6 | 1-methyl-1H-indole-3-carbonitrile | Drug Info | [5] | |||
| 7 | 1-methyl-1H-indole-3-carboxamide | Drug Info | [6] | |||
| 8 | 2-Benzyl-6-methoxy-5-oxazol-5-yl-1H-indole | Drug Info | [7] | |||
| 9 | 2-methyl-3-(pyridin-4-yl)-1H-indol-6-amine | Drug Info | [6] | |||
| 10 | 2-methyl-3-(pyridin-4-yl)-1H-indole | Drug Info | [6] | |||
| 11 | 3-(3-cyano-1H-indol-6-yl)-1-methyl-1-phenylurea | Drug Info | [5] | |||
| 12 | 3-(furan-3-yl)-1-methyl-1H-indole | Drug Info | [6] | |||
| 13 | 3-(furan-3-yl)-1H-indole | Drug Info | [6] | |||
| 14 | 3-(pyridin-4-yl)-1H-indol-6-amine | Drug Info | [6] | |||
| 15 | 3-(pyridin-4-yl)-1H-indol-7-amine | Drug Info | [6] | |||
| 16 | 3-(thiophen-3-yl)-1H-indol-6-amine | Drug Info | [6] | |||
| 17 | 3-methoxy-4-(oxazol-5-yl)aniline | Drug Info | [6] | |||
| 18 | 6-bromo-1-methyl-3-(pyridin-4-yl)-1H-indole | Drug Info | [6] | |||
| 19 | 6-bromo-3-(pyridin-4-yl)-1H-indole | Drug Info | [6] | |||
| 20 | 6-Chloropurine Riboside, 5'-Monophosphate | Drug Info | [8] | |||
| 21 | 6-Methoxy-5-oxazol-5-yl-2-phenyl-1H-indole | Drug Info | [7] | |||
| 22 | 6-phenyl-3-(pyridin-4-yl)-1H-indole | Drug Info | [5] | |||
| 23 | C2-MAD | Drug Info | [9] | |||
| 24 | C4-MAD | Drug Info | [9] | |||
| 25 | Ethyl 3-(pyridin-4-yl)-1H-indole-6-carboxylate | Drug Info | [5] | |||
| 26 | Inosinic Acid | Drug Info | [8] | |||
| 27 | Mycophenolic bis(sulfonamide) | Drug Info | [10] | |||
| 28 | Mycophenolic hydroxamic acid | Drug Info | [11] | |||
| 29 | N-benzyl-9-oxo-9,10-dihydroacridine-3-carboxamide | Drug Info | [12] | |||
| 30 | Nicotinamide-Adenine-Dinucleotide | Drug Info | [8] | |||
| 31 | Rockout | Drug Info | [5] | |||
| 32 | Selenazole-4-Carboxyamide-Adenine Dinucleotide | Drug Info | [8] | |||
| 33 | Tiazofurin adenine dinucleotide | Drug Info | [13] | |||
| 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: Adenosine triphosphate | Ligand Info | |||||
| Structure Description | Human IMPDH2 treated with ATP, IMP, and 20 mM GTP. Fully compressed filament segment reconstruction. | PDB:6UDO | ||||
| Method | Electron microscopy | Resolution | 3.21 Å | Mutation | No | [14] |
| PDB Sequence |
YVPDDGLTAQ
21 QLFNCGDGLT31 YNDFLILPGY41 IDFTADQVDL51 TSALTKKITL61 KTPLVSSPMD 71 TVTEAGMAIA81 MALTGGIGFI91 HHNCTPEFQA101 NEVRKVKKYE111 QGFITDPVVL 121 SPKDRVRDVF131 EAKARHGFCG141 IPITDTGRMG151 SRLVGIISSR161 DIDFLKEEEH 171 DCFLEEIMTK181 REDLVVAPAG191 ITLKEANEIL201 QRSKKGKLPI211 VNEDDELVAI 221 IARTDLKKNR231 DYPLASKDAK241 KQLLCGAAIG251 THEDDKYRLD261 LLAQAGVDVV 271 VLDSSQGNSI281 FQINMIKYIK291 DKYPNLQVIG301 GNVVTAAQAK311 NLIDAGVDAL 321 RVGMGSGSIC331 ITQEVLACGR341 PQATAVYKVS351 EYARRFGVPV361 IADGGIQNVG 371 HIAKALALGA381 STVMMGSLLA391 ATTEAPGEYF401 FSDGIRLKKY411 RGMGSLDAMI 437 KVAQGVSGAV447 QDKGSIHKFV457 PYLIAGIQHS467 CQDIGAKSLT477 QVRAMMYSGE 487 LKFEKRTSSA497 QVEGGVHSLH507 SYEKRLF
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: C2-MAD | Ligand Info | |||||
| Structure Description | Ternary complex of the human type II Inosine Monophosphate Dedhydrogenase with Ribavirin Monophosphate and C2-Mycophenolic Adenine Dinucleotide | PDB:1NF7 | ||||
| Method | X-ray diffraction | Resolution | 2.65 Å | Mutation | No | [15] |
| PDB Sequence |
TSYVPDDGLT
19 AQQLFNCGDG29 LTYNDFLILP39 GYIDFTADQV49 DLTSALTKKI59 TLKTPLVSSP 69 MDTVTEAGMA79 IAMALTGGIG89 FIHHNCTPEF99 QANEVRKVKK109 YEQGFITDPV 119 VLSPKGIISS160 RDIDFLEHDC173 FLEEIMTKRE183 DLVVAPAGIT193 LKEANEILQR 203 SKKGKLPIVN213 EDDELVAIIA223 RTLKKNRDYP234 LASKDAKKQL244 LCGAAIGTHE 254 DDKYRLDLLA264 QAGVDVVVLD274 SSQGNSIFQI284 NMIKYIKDKY294 PNLQVIGGNV 304 VTAAQAKNLI314 DAGVDALRVG324 MGSGSICITQ334 EVLACGRPQA344 TAVYKVSEYA 354 RRFGVPVIAD364 GGIQNVGHIA374 KALALGASTV384 MMGSLLAATT394 EAPGEYFFSD 404 GIRLKKYRGM414 GSLDAMIKVA440 QGVSGAVQDK450 GSIHKFVPYL460 IAGIQHSCQD 470 IGAKSLTQVR480 AMMYSGELKF490 EKRTSSAQVE500 GGVHSLHSYE510 KRLF |
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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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| Purine metabolism | hsa00230 | Affiliated Target |
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| Class: Metabolism => Nucleotide metabolism | Pathway Hierarchy | ||
| Drug metabolism - other enzymes | hsa00983 | Affiliated Target |
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| Class: Metabolism => Xenobiotics biodegradation and metabolism | Pathway Hierarchy | ||
| Degree | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 5.39E-05 |
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| Closeness centrality | 1.69E-01 | Radiality | 1.27E+01 | Clustering coefficient | 2.86E-01 |
| Neighborhood connectivity | 9.43E+00 | Topological coefficient | 2.73E-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 | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| BioCyc | [+] 6 BioCyc Pathways | + | ||||
| 1 | Purine nucleotides degradation | |||||
| 2 | Urate biosynthesis/inosine 5'-phosphate degradation | |||||
| 3 | Guanosine nucleotides de novo biosynthesis | |||||
| 4 | Superpathway of purine nucleotide salvage | |||||
| 5 | Purine nucleotides de novo biosynthesis | |||||
| 6 | Guanosine ribonucleotides de novo biosynthesis | |||||
| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Purine metabolism | |||||
| 2 | Drug metabolism - other enzymes | |||||
| 3 | Metabolic pathways | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | De novo purine biosynthesis | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Purine ribonucleoside monophosphate biosynthesis | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of Roche (2009). | |||||
| 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: 6831). | |||||
| REF 3 | Emerging drugs for idiopathic thrombocytopenic purpura in adults. Expert Opin Emerg Drugs. 2008 Jun;13(2):237-54. | |||||
| REF 4 | Inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitors: a patent and scientific literature review (2002-2016).Expert Opin Ther Pat. 2017 Jun;27(6):677-690. | |||||
| REF 5 | Novel indole inhibitors of IMPDH from fragments: synthesis and initial structure-activity relationships. Bioorg Med Chem Lett. 2006 May 1;16(9):2539-42. | |||||
| REF 6 | Low molecular weight indole fragments as IMPDH inhibitors. Bioorg Med Chem Lett. 2006 May 1;16(9):2535-8. | |||||
| REF 7 | Novel indole-based inhibitors of IMPDH: introduction of hydrogen bond acceptors at indole C-3. Bioorg Med Chem Lett. 2003 Apr 7;13(7):1273-6. | |||||
| REF 8 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 9 | Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia. J Med Chem. 2002 Jan 31;45(3):703-12. | |||||
| REF 10 | Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues: inhibition of inosine monophosphate dehydrogenase. Bioorg Med Chem. 2008 Aug 1;16(15):7462-9. | |||||
| REF 11 | Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase and differentiation induction of K562 cells among the mycoph... Bioorg Med Chem. 2010 Nov 15;18(22):8106-11. | |||||
| REF 12 | Acridone-based inhibitors of inosine 5'-monophosphate dehydrogenase: discovery and SAR leading to the identification of N-(2-(6-(4-ethylpiperazin-1... J Med Chem. 2007 Jul 26;50(15):3730-42. | |||||
| REF 13 | Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylases for cancer treatment. J Med Chem. 2007 Dec 27;50(26):6685-91. | |||||
| REF 14 | Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation. Elife. 2020 Jan 30;9:e53243. | |||||
| REF 15 | Crystal Structure of Human Inosine Monophosphate Dehydrogenase type II complexed with the MPA/NAD analog C2-MAD | |||||
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