Target Information
Target General Information | Top | |||||
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Target ID |
T89034
(Former ID: TTDS00392)
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Target Name |
Plasminogen (PLG)
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Synonyms |
Plasmin
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Gene Name |
PLG
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 6 Target-related Diseases | + | ||||
1 | Angina pectoris [ICD-11: BA40] | |||||
2 | Bleeding disorder [ICD-11: GA20-GA21] | |||||
3 | Menopausal disorder [ICD-11: GA30] | |||||
4 | Myocardial infarction [ICD-11: BA41-BA43] | |||||
5 | Procedure injury [ICD-11: NE81] | |||||
6 | Pulmonary thromboembolism [ICD-11: BB00] | |||||
Function |
In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells. Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation.
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BioChemical Class |
Peptidase
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UniProt ID | ||||||
EC Number |
EC 3.4.21.7
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Sequence |
MEHKEVVLLLLLFLKSGQGEPLDDYVNTQGASLFSVTKKQLGAGSIEECAAKCEEDEEFT
CRAFQYHSKEQQCVIMAENRKSSIIIRMRDVVLFEKKVYLSECKTGNGKNYRGTMSKTKN GITCQKWSSTSPHRPRFSPATHPSEGLEENYCRNPDNDPQGPWCYTTDPEKRYDYCDILE CEEECMHCSGENYDGKISKTMSGLECQAWDSQSPHAHGYIPSKFPNKNLKKNYCRNPDRE LRPWCFTTDPNKRWELCDIPRCTTPPPSSGPTYQCLKGTGENYRGNVAVTVSGHTCQHWS AQTPHTHNRTPENFPCKNLDENYCRNPDGKRAPWCHTTNSQVRWEYCKIPSCDSSPVSTE QLAPTAPPELTPVVQDCYHGDGQSYRGTSSTTTTGKKCQSWSSMTPHRHQKTPENYPNAG LTMNYCRNPDADKGPWCFTTDPSVRWEYCNLKKCSGTEASVVAPPPVVLLPDVETPSEED CMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPETNPRAGLEKNYCRNPDGDVGG PWCYTTNPRKLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRVVGGCVAHPHSWPWQVSLRT RFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLE PTRKDIALLKLSSPAVITDKVIPACLPSPNYVVADRTECFITGWGETQGTFGAGLLKEAQ LPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSW GLGCARPNKPGVYVRVSRFVTWIEGVMRNN Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T14JSX |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 8 Approved Drugs | + | ||||
1 | Alteplase | Drug Info | Approved | Pulmonary embolism | [2] | |
2 | Aminocaproic Acid | Drug Info | Approved | Bleeding disorder | [3] | |
3 | Anistreplase | Drug Info | Approved | Acute coronary syndrome | [4], [5] | |
4 | Ranolazine | Drug Info | Approved | Chronic/stable angina | [6], [7], [8] | |
5 | Reteplase | Drug Info | Approved | Heart attack | [5], [9] | |
6 | Streptokinase | Drug Info | Approved | Pulmonary embolism | [10] | |
7 | Tenecteplase | Drug Info | Approved | Myocardial infarction | [11] | |
8 | Tranexamic Acid | Drug Info | Approved | Excessive bleeding | [12], [13] | |
Clinical Trial Drug(s) | [+] 6 Clinical Trial Drugs | + | ||||
1 | Desmoteplase | Drug Info | Phase 3 | Ischemic stroke | [14] | |
2 | Plasminogen | Drug Info | Phase 2/3 | Alzheimer disease | [15] | |
3 | BIIB131 | Drug Info | Phase 2 | Acute ischemic stroke | [16] | |
4 | RetinoStat | Drug Info | Phase 2 | Macular degeneration | [17] | |
5 | Troplasminogen alfa | Drug Info | Phase 2 | Myocardial infarction | [18] | |
6 | bis-triazole derivative 10 | Drug Info | Clinical trial | Otitis media | [19] | |
Mode of Action | [+] 3 Modes of Action | + | ||||
Activator | [+] 8 Activator drugs | + | ||||
1 | Alteplase | Drug Info | [20] | |||
2 | Anistreplase | Drug Info | [23], [24] | |||
3 | Reteplase | Drug Info | [26], [27] | |||
4 | Streptokinase | Drug Info | [28] | |||
5 | Tenecteplase | Drug Info | [20] | |||
6 | Desmoteplase | Drug Info | [29] | |||
7 | BIIB131 | Drug Info | [32] | |||
8 | M5 | Drug Info | [25] | |||
Inhibitor | [+] 14 Inhibitor drugs | + | ||||
1 | Aminocaproic Acid | Drug Info | [21], [22] | |||
2 | Tranexamic Acid | Drug Info | [1] | |||
3 | MELAGATRAN | Drug Info | [30] | |||
4 | bis-triazole derivative 10 | Drug Info | [34] | |||
5 | 1-(2-Oxo-2-p-tolyl-ethyl)-1H-indole-2,3-dione | Drug Info | [35] | |||
6 | 1-(3,3-Dimethyl-2-oxo-butyl)-1H-indole-2,3-dione | Drug Info | [35] | |||
7 | 1-guanidino-7-isoquinolinesulphonamide | Drug Info | [36] | |||
8 | 1-guanidino-N-phenyl-7-isoquinolinesulphonamide | Drug Info | [36] | |||
9 | 2-(2-Hydroxy-phenyl)-1H-indole-5-carboxamidine | Drug Info | [37] | |||
10 | Bicine | Drug Info | [38] | |||
11 | Grassystatin a | Drug Info | [39] | |||
12 | N-(4-Chloro-7-p-tolyl-isoquinolin-1-yl)-guanidine | Drug Info | [40] | |||
13 | Textilinin | Drug Info | [25] | |||
14 | XP-21510 | Drug Info | [25] | |||
Modulator | [+] 5 Modulator drugs | + | ||||
1 | Ranolazine | Drug Info | [25] | |||
2 | Plasminogen | Drug Info | [25], [31] | |||
3 | RetinoStat | Drug Info | [17] | |||
4 | Troplasminogen alfa | Drug Info | [25], [33] | |||
5 | SMTP-0 | Drug Info | [25] |
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 | THE STRUCTURE OF THE NON-COVALENT COMPLEX OF RECOMBINANT KRINGLE 1 DOMAIN OF HUMAN PLASMINOGEN WITH EACA (EPSILON-AMINOCAPROIC ACID) | PDB:1CEA | ||||
Method | X-ray diffraction | Resolution | 2.06 Å | Mutation | No | [41] |
PDB Sequence |
ECKTGNGKNY
9 RGTMSKTKNG19 ITCQKWSSTS29 PHRPRFSPAT39 HPSEGLEENY49 CRNPDNDPQG 59 PWCYTTDPEK69 RYDYCDILEC79
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Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
Ligand Name: Tranexamic acid | Ligand Info | |||||
Structure Description | THE STRUCTURE OF THE NON-COVALENT COMPLEX OF RECOMBINANT KRINGLE 1 DOMAIN OF HUMAN PLASMINOGEN WITH AMCHA (TRANS-4-AMINOMETHYLCYCLOHEXANE-1-CARBOXYLIC ACID) | PDB:1CEB | ||||
Method | X-ray diffraction | Resolution | 2.07 Å | Mutation | No | [41] |
PDB Sequence |
ECKTGNGKNY
9 RGTMSKTKNG19 ITCQKWSSTS29 PHRPRFSPAT39 HPSEGLEENY49 CRNPDNDPQG 59 PWCYTTDPEK69 RYDYCDILEC79
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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 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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Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
Complement and coagulation cascades | hsa04610 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy |
Degree | 32 | Degree centrality | 3.44E-03 | Betweenness centrality | 3.25E-03 |
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Closeness centrality | 2.31E-01 | Radiality | 1.41E+01 | Clustering coefficient | 4.23E-02 |
Neighborhood connectivity | 1.42E+01 | Topological coefficient | 4.95E-02 | 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 |
Co-Targets | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | Evaluation of aprotinin and tranexamic acid in different in vitro and in vivo models of fibrinolysis, coagulation and thrombus formation. J Thromb Haemost. 2007 Oct;5(10):2113-8. | |||||
REF 2 | Emerging drugs in peripheral arterial disease. Expert Opin Emerg Drugs. 2006 Mar;11(1):75-90. | |||||
REF 3 | The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954. | |||||
REF 4 | Acylated plasminogen-streptokinase activator complex: a new approach to thrombolytic therapy. Pharmacotherapy. 1990;10(2):115-26. | |||||
REF 5 | Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. | |||||
REF 6 | 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: 7291). | |||||
REF 7 | 2006 drug approvals: finding the niche. Nat Rev Drug Discov. 2007 Feb;6(2):99-101. | |||||
REF 8 | Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload. Heart. 2006 Jul;92 Suppl 4:iv1-iv5. | |||||
REF 9 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
REF 10 | Emerging drugs for chemotherapy-induced mucositis. Expert Opin Emerg Drugs. 2008 Sep;13(3):511-22. | |||||
REF 11 | Fibrinolytic agents for the management of ST-segment elevation myocardial infarction. Pharmacotherapy. 2007 Nov;27(11):1558-70. | |||||
REF 12 | 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: 6573). | |||||
REF 13 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 019281. | |||||
REF 14 | ClinicalTrials.gov (NCT00111852) Study of Desmoteplase (International Nonproprietary Name [INN]) in Acute Ischemic Stroke (DIAS-2). U.S. National Institutes of Health. | |||||
REF 15 | ClinicalTrials.gov (NCT01554956) Efficacy/Safety of Human Plasminogen Eye Drop in Ligneous Conjunctivitis Patients. U.S. National Institutes of Health. | |||||
REF 16 | ClinicalTrials.gov (NCT05764122) A Multicenter, Operationally Seamless, Double-Blind, Dose-Ranging, Placebo-Controlled, Randomized, Parallel-Group, Phase 2b Study to Evaluate the Efficacy and Safety of Intravenous BIIB131 for Participants With Ischemic Stroke Between 4.5 and 24 Hours After Last Known Well. U.S.National Institutes of Health. | |||||
REF 17 | Safety and biodistribution of an equine infectious anemia virus-based gene therapy, RetinoStat( ), for age-related macular degeneration. Hum Gene Ther. 2012 Sep;23(9):980-91. | |||||
REF 18 | ClinicalTrials.gov (NCT00144014) Safety and Efficacy Study in Acute Ischaemic Stroke. U.S. National Institutes of Health. | |||||
REF 19 | 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: 6537). | |||||
REF 20 | Thrombolytic therapies: the current state of affairs. J Endovasc Ther. 2005 Apr;12(2):224-32. | |||||
REF 21 | The blockage of the high-affinity lysine binding sites of plasminogen by EACA significantly inhibits prourokinase-induced plasminogen activation. Biochim Biophys Acta. 2002 Apr 29;1596(2):182-92. | |||||
REF 22 | Analysis of plasmin binding and urokinase activation of plasminogen bound to the Heymann nephritis autoantigen, gp330. Arch Biochem Biophys. 1992 Dec;299(2):255-60. | |||||
REF 23 | Evaluation of thrombolytic agents. Drugs. 1997;54 Suppl 3:11-6; discussion 16-7. | |||||
REF 24 | Therapeutic management of acute myocardial infarction. Am J Hosp Pharm. 1990 Sep;47(9 Suppl 2):S5-10. | |||||
REF 25 | Tranexamic acid in trauma: how should we use it. J Trauma Acute Care Surg. 2013 Jun;74(6):1575-86. | |||||
REF 26 | Fibrin binding and the regulation of plasminogen activators during thrombolytic therapy. Cardiovasc Hematol Agents Med Chem. 2008 Jul;6(3):212-23. | |||||
REF 27 | Spotlight on reteplase in thrombotic occlusive disorders. BioDrugs. 2007;21(1):65-8. | |||||
REF 28 | Acute anuric renal failure with streptokinase therapy in a patient with acute venous thromboembolic disease and the review of renal side effects of streptokinase. Tuberk Toraks. 2008;56(4):456-61. | |||||
REF 29 | Vampire bat salivary plasminogen activator (desmoteplase): a unique fibrinolytic enzyme that does not promote neurodegeneration. Stroke. 2003 Feb;34(2):537-43. | |||||
REF 30 | Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety. Bioorg Med Chem Lett. 2006 May 15;16(10):2641-7. | |||||
REF 31 | Structure and function of the plasminogen/plasmin system. Thromb Haemost. 2005 Apr;93(4):647-54. | |||||
REF 32 | Clinical pipeline report, company report or official report of Biogen | |||||
REF 33 | V-10153 (Vernalis). Curr Opin Investig Drugs. 2005 Sep;6(9):951-5. | |||||
REF 34 | A new strategy for the development of highly potent and selective plasmin inhibitors. J Med Chem. 2012 Feb 9;55(3):1171-80. | |||||
REF 35 | Parallel synthesis of isatin-based serine protease inhibitors. Bioorg Med Chem Lett. 2000 Nov 20;10(22):2501-4. | |||||
REF 36 | Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines. J Med Chem. 2007 May 17;50(10):2341-51. | |||||
REF 37 | 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 38 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
REF 39 | Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation. J Med Chem. 2009 Sep 24;52(18):5732-47. | |||||
REF 40 | Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-isoquinolinylguanidines. Bioorg Med Chem Lett. 2004 Jun 21;14(12):3227-30. | |||||
REF 41 | Crystal structures of the recombinant kringle 1 domain of human plasminogen in complexes with the ligands epsilon-aminocaproic acid and trans-4-(aminomethyl)cyclohexane-1-carboxylic Acid. Biochemistry. 1996 Feb 27;35(8):2567-76. |
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