Target Information
| Target General Information | Top | |||||
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| Target ID |
T28265
(Former ID: TTDS00285)
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| Target Name |
Alpha-1-antitrypsin (SERPINA1)
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| Synonyms |
SERPINA1; PRO0684/PRO2209; Alpha1-proteinase; Alpha-1-antiproteinase; Alpha-1 protease inhibitor
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| Gene Name |
SERPINA1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Emphysema [ICD-11: CA21] | |||||
| Function |
Inhibitor of serine proteases. Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin.
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| BioChemical Class |
Serpin protein
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| UniProt ID | ||||||
| Sequence |
MPSSVSWGILLLAGLCCLVPVSLAEDPQGDAAQKTDTSHHDQDHPTFNKITPNLAEFAFS
LYRQLAHQSNSTNIFFSPVSIATAFAMLSLGTKADTHDEILEGLNFNLTEIPEAQIHEGF QELLRTLNQPDSQLQLTTGNGLFLSEGLKLVDKFLEDVKKLYHSEAFTVNFGDTEEAKKQ INDYVEKGTQGKIVDLVKELDRDTVFALVNYIFFKGKWERPFEVKDTEEEDFHVDQVTTV KVPMMKRLGMFNIQHCKKLSSWVLLMKYLGNATAIFFLPDEGKLQHLENELTHDIITKFL ENEDRRSASLHLPKLSITGTYDLKSVLGQLGITKVFSNGADLSGVTEEAPLKLSKAVHKA VLTIDEKGTEAAGAMFLEAIPMSIPPEVKFNKPFVFLMIEQNTKSPLFMGKVVNPTQK Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T91MLF | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Glassia | Drug Info | Approved | Emphysema | [1], [2] | |
| 2 | Zemaira | Drug Info | Approved | Emphysema | [3] | |
| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | AGTC-0106 | Drug Info | Phase 2 | Alpha-1 antitrypsin deficiency | [4] | |
| 2 | Igmesine | Drug Info | Phase 2 | Major depressive disorder | [5] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | Glassia | Drug Info | [1] | |||
| 2 | Zemaira | Drug Info | [3] | |||
| 3 | 2-Sulfhydryl-Ethanol | Drug Info | [8] | |||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | AGTC-0106 | Drug Info | [6] | |||
| 2 | Igmesine | 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: Oxamic acid | Ligand Info | |||||
| Structure Description | Crystal structure of native alpha-1-antitrypsin with seven stabilising mutations | PDB:5NBU | ||||
| Method | X-ray diffraction | Resolution | 1.67 Å | Mutation | Yes | [9] |
| PDB Sequence |
TFNKITPNLA
31 EFAFSLYRQL41 AHQSNSTNIL51 FSPVSIAAAF61 AMLSLGAKGD71 THDEILEGLN 81 FNLTEIPEAQ91 IHEGFQELLR101 TLNQSQLQLT113 TGNGLFLSEG123 LKLVDKFLED 133 VKKLYHSEAF143 TVNFGDTEEA153 KKQINDYVEK163 GTQGKIVDLV173 KELDRDTVFA 183 LVNYIFFKGK193 WERPFEVKDT203 EEEDFHVDQV213 TTVKVPMMKR223 LGMFNIQHSK 233 KLSSWVLLMK243 YLGNATAIFF253 LPDEGKLQHL263 ENELTHDIIT273 KFLENEDRRS 283 ASLHLPKLSI293 TGTYDLKSVL303 GQLGITKVFS313 NGADLSGVTE323 EAPLKLSKAV 333 HKAVLTIDEK343 GTEAAGAMFL353 EAIPMSIPPE363 VKFNKPFVFL373 IIEQNTKAPL 383 FMGRVVNPTQ393
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| Ligand Name: 3-(Trimethylsilyl)propane-1-sulfonic acid | Ligand Info | |||||
| Structure Description | Alpha-1-antitrypsin Queen's (K154N) variant | PDB:6I4V | ||||
| Method | X-ray diffraction | Resolution | 1.78 Å | Mutation | Yes | [10] |
| PDB Sequence |
NKITPNLAEF
33 AFSLYRQLAH43 QSNSTNIFFS53 PVSIATAFAM63 LSLGTKADTH73 DEILEGLNFN 83 LTEIPEAQIH93 EGFQELLRTL103 NQPDSQLQLT113 TGNGLFLSEG123 LKLVDKFLED 133 VKKLYHSEAF143 TVNFGDTEEA153 NKQINDYVEK163 GTQGKIVDLV173 KELDRDTVFA 183 LVNYIFFKGK193 WERPFEVKDT203 EEEDFHVDQV213 TTVKVPMMKR223 LGMFNIQHSK 233 KLSSWVLLMK243 YLGNATAIFF253 LPDEGKLQHL263 ENELTHDIIT273 KFLENEDRRS 283 ASLHLPKLSI293 TGTYDLKSVL303 GQLGITKVFS313 NGADLSGVTE323 EAPLKLSKAV 333 HKAVLTIDEK343 GTEAAGAMFL353 EAIPMSIPPE363 VKFNKPFVFL373 MIEQNTKSPL 383 FMGKVVNPTQ393 K
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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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| Complement and coagulation cascades | hsa04610 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 3.24E-04 |
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| Closeness centrality | 1.95E-01 | Radiality | 1.33E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.01E+01 | Topological coefficient | 1.58E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Complement and coagulation cascades | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | IL6 Signaling Pathway | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Blood coagulation | |||||
| PID Pathway | [+] 2 PID Pathways | + | ||||
| 1 | p73 transcription factor network | |||||
| 2 | FOXA1 transcription factor network | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | Platelet degranulation | |||||
| 2 | COPII (Coat Protein 2) Mediated Vesicle Transport | |||||
| 3 | Cargo concentration in the ER | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | Complement and Coagulation Cascades | |||||
| 2 | NRF2 pathway | |||||
| 3 | Nuclear Receptors Meta-Pathway | |||||
| References | Top | |||||
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| REF 1 | Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5. | |||||
| 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: 7487). | |||||
| REF 3 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. | |||||
| REF 4 | ClinicalTrials.gov (NCT01054339) Safety & Efficacy Study of rAAV1-CB-hAAT for Alpha-1 Antitrypsin Deficiency. U.S. National Institutes of Health. | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001429) | |||||
| REF 6 | First gene therapy nears landmark European market authorization. Nat Biotechnol. 2012 Sep;30(9):807-9. | |||||
| REF 7 | Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91. | |||||
| REF 8 | DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41. | |||||
| REF 9 | CRYSTAL STRUCTURE OF THE Z VARIANT OF ALPHA-1-ANTITRYPSIN REVEALS STRUCTURAL AND DYNAMICAL CHANGES AND SUPPORTS A C-TERMINAL DOMAIN SWAP MECHANISM OF POLYMERIZATION | |||||
| REF 10 | Structural determinants of instability in alpha-1-antitrypsin | |||||
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