Target Information
| Target General Information | Top | |||||
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| Target ID |
T98896
(Former ID: TTDR00697)
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| Target Name |
Aggrecanase (ADAMTS5)
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| Synonyms |
Aggrecanase-2; ADMP-2; ADAMTS5; ADAMTS-5; ADAM-TS5; ADAM-TS 5; ADAM-TS 11; A disintegrin and metalloproteinase with thrombospondinmotifs 5
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| Gene Name |
ADAMTS5
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Osteoarthritis [ICD-11: FA00-FA05] | |||||
| Function |
Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases. May play a role in proteolytic processing mostly during the peri-implantation period.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.24.-
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| Sequence |
MLLGWASLLLCAFRLPLAAVGPAATPAQDKAGQPPTAAAAAQPRRRQGEEVQERAEPPGH
PHPLAQRRRSKGLVQNIDQLYSGGGKVGYLVYAGGRRFLLDLERDGSVGIAGFVPAGGGT SAPWRHRSHCFYRGTVDGSPRSLAVFDLCGGLDGFFAVKHARYTLKPLLRGPWAEEEKGR VYGDGSARILHVYTREGFSFEALPPRASCETPASTPEAHEHAPAHSNPSGRAALASQLLD QSALSPAGGSGPQTWWRRRRRSISRARQVELLLVADASMARLYGRGLQHYLLTLASIANR LYSHASIENHIRLAVVKVVVLGDKDKSLEVSKNAATTLKNFCKWQHQHNQLGDDHEEHYD AAILFTREDLCGHHSCDTLGMADVGTICSPERSCAVIEDDGLHAAFTVAHEIGHLLGLSH DDSKFCEETFGSTEDKRLMSSILTSIDASKPWSKCTSATITEFLDDGHGNCLLDLPRKQI LGPEELPGQTYDATQQCNLTFGPEYSVCPGMDVCARLWCAVVRQGQMVCLTKKLPAVEGT PCGKGRICLQGKCVDKTKKKYYSTSSHGNWGSWGSWGQCSRSCGGGVQFAYRHCNNPAPR NNGRYCTGKRAIYRSCSLMPCPPNGKSFRHEQCEAKNGYQSDAKGVKTFVEWVPKYAGVL PADVCKLTCRAKGTGYYVVFSPKVTDGTECRLYSNSVCVRGKCVRTGCDGIIGSKLQYDK CGVCGGDNSSCTKIVGTFNKKSKGYTDVVRIPEGATHIKVRQFKAKDQTRFTAYLALKKK NGEYLINGKYMISTSETIIDINGTVMNYSGWSHRDDFLHGMGYSATKEILIVQILATDPT KPLDVRYSFFVPKKSTPKVNSVTSHGSNKVGSHTSQPQWVTGPWLACSRTCDTGWHTRTV QCQDGNRKLAKGCPLSQRPSAFKQCLLKKC Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T34U48 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | AGG-523 | Drug Info | Phase 1 | Osteoarthritis | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 4 Inhibitor drugs | + | ||||
| 1 | AGG-523 | Drug Info | [1] | |||
| 2 | SC-44463 | Drug Info | [3] | |||
| 3 | CR-5259 | Drug Info | [4] | |||
| 4 | PMID21536437C15c | Drug Info | [5] | |||
| 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: Marimastat | Ligand Info | |||||
| Structure Description | Crystal Structure of the Catalytic Domain of ADAMTS-5 in Complex with Marimastat | PDB:3HY7 | ||||
| Method | X-ray diffraction | Resolution | 1.69 Å | Mutation | Yes | [6] |
| PDB Sequence |
SRARQVELLL
273 VADASMARKY283 GRGLQHYLLT293 LASIANRLYS303 HASIENHIRL313 AVVKVVVLGD 323 KDKSLEVSKN333 AATTLKNFCK343 WQHQHNQLGD353 DHEEHYDAAI363 LFTREDLCGH 373 HSCDTLGMAD383 VGTICSPERS393 CAVIEDDGLH403 AAFTVAHEIG413 HLLGLSHDDS 423 KFCEETFGST433 EDKRLMSSIL443 TSIDASKPWS453 KCTSATITEF463 LDDGHGNCLL 473 DLPRKQI
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| Ligand Name: Batimastat | Ligand Info | |||||
| Structure Description | Crystal structure of ADAMTS5 with inhibitor bound | PDB:2RJQ | ||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [7] |
| PDB Sequence |
SRARQVELLL
273 VADASMARLY283 GRGLQHYLLT293 LASIANRLYS303 HASIENHIRL313 AVVKVVVLGD 323 KDKSLEVSKN333 AATTLKNFCK343 WQHQHNQLGD353 DHEEHYDAAI363 LFTREDLCGH 373 HSCDTLGMAD383 VGTICSPERS393 CAVIEDDGLH403 AAFTVAHEIG413 HLLGLSHDDS 423 KFCEETFGST433 EDKRLMSSIL443 TSIDASKPWS453 KCTSATITEF463 LDDGHGNCLL 473 DLPRKQILGP483 EELPGQTYDA493 TQQCNLTFGP503 EYSVCPGMDV513 CARLWCAVVR 523 QGQMVCLTKK533 LPAVEGTPCG543 KGRICLQGKC553 VD
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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).
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
Biological Network Descriptors
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Netrin receptor UNC5A (UNC5A) | 36.000 (18/50) | 4.82E-04 |
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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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| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 1.29E-06 |
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| Closeness centrality | 1.71E-01 | Radiality | 1.27E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.15E+01 | Topological coefficient | 5.53E-01 | Eccentricity | 13 |
| 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 Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Degradation of the extracellular matrix | |||||
| 2 | O-glycosylation of TSR domain-containing proteins | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Endochondral Ossification | |||||
| 2 | Vitamin D Receptor Pathway | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor. Osteoarthritis Cartilage. 2011 Mar;19(3):315-23. | |||||
| REF 2 | ClinicalTrials.gov (NCT00454298) Study Evaluating AGG-523 in Subjects With Severe Osteoarthritis Requiring Total Knee Replacement. U.S. National Institutes of Health. | |||||
| REF 3 | Design and synthesis of a series of (2R)-N(4)-hydroxy-2-(3-hydroxybenzyl)-N(1)- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide derivati... J Med Chem. 2001 Oct 11;44(21):3347-50. | |||||
| REF 4 | 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. (Target id: 1677). | |||||
| REF 5 | Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis. Bioorg Med Chem Lett. 2011 Jun 1;21(11):3301-6. | |||||
| REF 6 | Structural and inhibition analysis reveals the mechanism of selectivity of a series of aggrecanase inhibitors. J Biol Chem. 2009 Sep 4;284(36):24185-91. | |||||
| REF 7 | Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5. Protein Sci. 2008 Jan;17(1):16-21. | |||||
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