Target Information
| Target General Information | Top | |||||
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| Target ID |
T45299
(Former ID: TTDR01233)
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| Target Name |
Tissue-type plasminogen activator (PLAT)
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| Synonyms |
TPA; T-plasminogen activator; T-PA; Reteplase; Alteplase
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| Gene Name |
PLAT
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Bleeding disorder [ICD-11: GA20-GA21] | |||||
| 2 | Procedure injury [ICD-11: NE81] | |||||
| Function |
By controlling plasmin-mediated proteolysis, it plays an important role in tissue remodeling and degradation, in cell migration and many other physiopathological events. Plays a direct role in facilitating neuronal migration. Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.21.68
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| Sequence |
MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRRGARSYQVICRDEKTQMIYQQHQSWLRPV
LRSNRVEYCWCNSGRAQCHSVPVKSCSEPRCFNGGTCQQALYFSDFVCQCPEGFAGKCCE IDTRATCYEDQGISYRGTWSTAESGAECTNWNSSALAQKPYSGRRPDAIRLGLGNHNYCR NPDRDSKPWCYVFKAGKYSSEFCSTPACSEGNSDCYFGNGSAYRGTHSLTESGASCLPWN SMILIGKVYTAQNPSAQALGLGKHNYCRNPDGDAKPWCHVLKNRRLTWEYCDVPSCSTCG LRQYSQPQFRIKGGLFADIASHPWQAAIFAKHRRSPGERFLCGGILISSCWILSAAHCFQ ERFPPHHLTVILGRTYRVVPGEEEQKFEVEKYIVHKEFDDDTYDNDIALLQLKSDSSRCA QESSVVRTVCLPPADLQLPDWTECELSGYGKHEALSPFYSERLKEAHVRLYPSSRCTSQH LLNRTVTDNMLCAGDTRSGGPQANLHDACQGDSGGPLVCLNDGRMTLVGIISWGLGCGQK DVPGVYTKVTNYLDWIRDNMRP Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T00EP2 | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Aminocaproic Acid | Drug Info | Approved | Bleeding disorder | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 9 Inhibitor drugs | + | ||||
| 1 | Aminocaproic Acid | Drug Info | [1] | |||
| 2 | 1-guanidino-N-phenyl-7-isoquinolinesulphonamide | Drug Info | [3] | |||
| 3 | 2-(2-Hydroxy-phenyl)-1H-indole-5-carboxamidine | Drug Info | [4] | |||
| 4 | 5-(DIMETHYLAMINO)-2-NAPHTHALENESULFONIC ACID | Drug Info | [5] | |||
| 5 | BMS-344577 | Drug Info | [6] | |||
| 6 | N-(4-Chloro-7-p-tolyl-isoquinolin-1-yl)-guanidine | Drug Info | [7] | |||
| 7 | N-(4-Phenyl-pyridin-2-yl)-guanidine | Drug Info | [8] | |||
| 8 | N-(5-Benzyloxy-isoquinolin-1-yl)-guanidine | Drug Info | [7] | |||
| 9 | N-(7-Benzyloxy-isoquinolin-1-yl)-guanidine | Drug Info | [7] | |||
| 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: Aminocaproic acid | Ligand Info | |||||
| Structure Description | SOLUTION STRUCTURE OF THE TISSUE-TYPE PLASMINOGEN ACTIVATOR KRINGLE 2 DOMAIN COMPLEXED TO 6-AMINOHEXANOIC ACID AN ANTIFIBRINOLYTIC DRUG | PDB:1PK2 | ||||
| Method | Solution NMR | Resolution | N.A. | Mutation | No | [9] |
| PDB Sequence |
SEGNSDCYFG
10 NGSAYRGTHS20 LTESGASCLP30 WNSMILIGKV40 YTAQNPSAQA50 LGLGKHNYCR 60 NPDGDAKPWC70 HVLKNRRLTW80 EYCDVPSCST90
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| Ligand Name: Benzamidine | Ligand Info | |||||
| Structure Description | COMPLEX OF BENZAMIDINE WITH THE CATALYTIC DOMAIN OF HUMAN TWO CHAIN TISSUE PLASMINOGEN ACTIVATOR [(TC)-T-PA] | PDB:1RTF | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [10] |
| PDB Sequence |
IKGGLFADIA
25 SHPWQAAIFA35 KHRGERFLCG43 GILISSCWIL53 SAAHCFQERF60C PPHHLTVILG 69 RTYRVVPGEE79 EQKFEVEKYI89 VHKEFDDDTY99 DNDIALLQLK109 SDSSRCAQES 115 SVVRTVCLPP125 ADLQLPDWTE135 CELSGYGKHE145 ALSPFYSERL155 KEAHVRLYPS 165 SRCTSQHLLN173 RTVTDNMLCA183 GDTRSNLHDA190 CQGDSGGPLV200 CLNDGRMTLV 210 GIISWGLGCG221 QKDVPGVYTK230 VTNYLDWIRD240 NMRP
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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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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Aggrecan core protein (ACAN) | 35.616 (26/73) | 4.00E-03 |
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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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| Apelin signaling pathway | hsa04371 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Complement and coagulation cascades | hsa04610 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 10 | Degree centrality | 1.07E-03 | Betweenness centrality | 3.26E-04 |
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| Closeness centrality | 2.04E-01 | Radiality | 1.35E+01 | Clustering coefficient | 6.67E-02 |
| Neighborhood connectivity | 1.03E+01 | Topological coefficient | 1.24E-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-regulating Transcription Factors | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Complement and coagulation cascades | |||||
| 2 | Transcriptional misregulation in cancer | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | IL5 Signaling Pathway | |||||
| Panther Pathway | [+] 2 Panther Pathways | + | ||||
| 1 | Blood coagulation | |||||
| 2 | Plasminogen activating cascade | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Coagulation | |||||
| PID Pathway | [+] 2 PID Pathways | + | ||||
| 1 | amb2 Integrin signaling | |||||
| 2 | Beta2 integrin cell surface interactions | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Dissolution of Fibrin Clot | |||||
| WikiPathways | [+] 8 WikiPathways | + | ||||
| 1 | Senescence and Autophagy in Cancer | |||||
| 2 | Complement and Coagulation Cascades | |||||
| 3 | Endochondral Ossification | |||||
| 4 | Blood Clotting Cascade | |||||
| 5 | Dissolution of Fibrin Clot | |||||
| 6 | Folate Metabolism | |||||
| 7 | Vitamin B12 Metabolism | |||||
| 8 | Selenium Micronutrient Network | |||||
| 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 | The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954. | |||||
| REF 3 | Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines. J Med Chem. 2007 May 17;50(10):2341-51. | |||||
| REF 4 | Development of serine protease inhibitors displaying a multicentered short (<2.3 A) hydrogen bond binding mode: inhibitors of urokinase-type plasmi... J Med Chem. 2001 Aug 16;44(17):2753-71. | |||||
| REF 5 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 6 | Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577. Bioorg Med Chem Lett. 2009 Dec 15;19(24):6882-9. | |||||
| REF 7 | Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-isoquinolinylguanidines. Bioorg Med Chem Lett. 2004 Jun 21;14(12):3227-30. | |||||
| REF 8 | Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 1: 2-Pyridinylguanidines. Bioorg Med Chem Lett. 2002 Jan 21;12(2):181-4. | |||||
| REF 9 | Solution structure of the tissue-type plasminogen activator kringle 2 domain complexed to 6-aminohexanoic acid an antifibrinolytic drug. J Mol Biol. 1991 Dec 20;222(4):1035-51. | |||||
| REF 10 | The 2.3 A crystal structure of the catalytic domain of recombinant two-chain human tissue-type plasminogen activator. J Mol Biol. 1996 Apr 26;258(1):117-35. | |||||
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