Target Information
Target General Information | Top | |||||
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Target ID |
T22976
(Former ID: TTDR00783)
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Target Name |
Thymidine kinase 2 (Mt-TK2)
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Synonyms |
dnk; Multispecific deoxynucleoside kinase; Dm-Dnk; Deoxyribonucleoside kinase
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Gene Name |
dnk
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Inborn purine/pyrimidine/nucleotide metabolism error [ICD-11: 5C55] | |||||
Function |
Deoxyribonucleoside kinase that has a broad specificity phosphorylating thymidine, deoxyadenosine, deoxycytidine and deoxyguanosine. Specificity is higher for pyrimidine nucleosides. Several anti-viral and anti-cancer nucleoside analogs are also efficiently phosphorylated.
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BioChemical Class |
Kinase
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UniProt ID | ||||||
EC Number |
EC 2.7.1.21
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Sequence |
MLLWPLRGWAARALRCFGPGSRGSPASGPGPRRVQRRAWPPDKEQEKEKKSVICVEGNIA
SGKTTCLEFFSNATDVEVLTEPVSKWRNVRGHNPLGLMYHDASRWGLTLQTYVQLTMLDR HTRPQVSSVRLMERSIHSARYIFVENLYRSGKMPEVDYVVLSEWFDWILRNMDVSVDLIV YLRTNPETCYQRLKKRCREEEKVIPLEYLEAIHHLHEEWLIKGSLFPMAAPVLVIEADHH MERMLELFEQNRDRILTPENRKHCP Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
ADReCS ID | BADD_A05311 |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
1 | MT-1621 | Drug Info | Phase 3 | Thymidine kinase 2 deficiency | [2] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Replacement | [+] 1 Replacement drugs | + | ||||
1 | MT-1621 | Drug Info | [3] | |||
Inhibitor | [+] 3 Inhibitor drugs | + | ||||
1 | 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine | Drug Info | [1] | |||
2 | 1-[5-(triphenylmethoxy)pentyl]thymine | Drug Info | [1] | |||
3 | 1-[6-(triphenylmethoxy)hexyl]thymine | Drug Info | [1] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
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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Pyrimidine metabolism | hsa00240 | 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 | 6 | Degree centrality | 6.45E-04 | Betweenness centrality | 3.33E-04 |
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Closeness centrality | 1.84E-01 | Radiality | 1.31E+01 | Clustering coefficient | 4.67E-01 |
Neighborhood connectivity | 1.23E+01 | Topological coefficient | 2.57E-01 | Eccentricity | 11 |
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-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | N1-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors. J Med Chem. 2006 Dec 28;49(26):7766-73. | |||||
REF 2 | ClinicalTrials.gov (NCT04581733) A Study of the Efficacy and Safety of MT1621 in Thymidine Kinase 2 (TK2) Deficiency. U.S. National Institutes of Health. | |||||
REF 3 | Clinical pipeline report, company report or official report of Modis Therapeutics. |
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