Target Information
| Target General Information | Top | |||||
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| Target ID |
T79570
(Former ID: TTDR00696)
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| Target Name |
Aggrecanase-1 (ADAMTS4)
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| Synonyms |
Aggrecanase 1; ADMP-1; ADAMTS4; ADAM-TS4; ADAM-TS 4; A disintegrin and metalloproteinase with thrombospondin motifs 4
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| Gene Name |
ADAMTS4
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| Target Type |
Patented-recorded target
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[1] | ||||
| 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. Could also be a critical factor in the exacerbation of neurodegeneration in Alzheimer disease. Cleaves aggrecan at the '392-Glu-|-Ala-393' site.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.24.82
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| Sequence |
MSQTGSHPGRGLAGRWLWGAQPCLLLPIVPLSWLVWLLLLLLASLLPSARLASPLPREEE
IVFPEKLNGSVLPGSGAPARLLCRLQAFGETLLLELEQDSGVQVEGLTVQYLGQAPELLG GAEPGTYLTGTINGDPESVASLHWDGGALLGVLQYRGAELHLQPLEGGTPNSAGGPGAHI LRRKSPASGQGPMCNVKAPLGSPSPRPRRAKRFASLSRFVETLVVADDKMAAFHGAGLKR YLLTVMAAAAKAFKHPSIRNPVSLVVTRLVILGSGEEGPQVGPSAAQTLRSFCAWQRGLN TPEDSDPDHFDTAILFTRQDLCGVSTCDTLGMADVGTVCDPARSCAIVEDDGLQSAFTAA HELGHVFNMLHDNSKPCISLNGPLSTSRHVMAPVMAHVDPEEPWSPCSARFITDFLDNGY GHCLLDKPEAPLHLPVTFPGKDYDADRQCQLTFGPDSRHCPQLPPPCAALWCSGHLNGHA MCQTKHSPWADGTPCGPAQACMGGRCLHMDQLQDFNIPQAGGWGPWGPWGDCSRTCGGGV QFSSRDCTRPVPRNGGKYCEGRRTRFRSCNTEDCPTGSALTFREEQCAAYNHRTDLFKSF PGPMDWVPRYTGVAPQDQCKLTCQAQALGYYYVLEPRVVDGTPCSPDSSSVCVQGRCIHA GCDRIIGSKKKFDKCMVCGGDGSGCSKQSGSFRKFRYGYNNVVTIPAGATHILVRQQGNP GHRSIYLALKLPDGSYALNGEYTLMPSPTDVVLPGAVSLRYSGATAASETLSGHGPLAQP LTLQVLVAGNPQDTRLRYSFFVPRPTPSTPRPTPQDWLHRRAQILEILRRRPWAGRK Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| 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: N-({4'-[(4-Isobutyrylphenoxy)methyl]biphenyl-4-Yl}sulfonyl)-D-Valine | Ligand Info | |||||
| Structure Description | Crystal structure of ADAMTS4 with inhibitor bound | PDB:2RJP | ||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | Yes | [4] |
| PDB Sequence |
ASLSRFVETL
223 VVADDKMAAF233 HGAGLKRYLL243 TVMAAAAKAF253 KHPSIRNPVS263 LVVTRLVILE 277 GPQVGPSAAQ287 TLRSFCAWQR297 GLNTPEDSDP307 DHFDTAILFT317 RQDLCGVSTC 327 DTLGMADVGT337 VCDPARSCAI347 VEDDGLQSAF357 TAAHQLGHVF367 NMLHDNSKPC 377 ISLNGPLSTS387 RHVMAPVMAH397 VDPEEPWSPC407 SARFITDFLD417 NGYGHCLLDK 427 PEAPLHLPVT437 FPGKDYDADR447 QCQLTFGPDS457 RHCPQLPPPC467 AALWCSGHLN 477 GHAMCQTKHS487 PWADGTPCGP497 AQACMGGRCL507 H
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ALA248
3.957
ALA252
3.526
ASP328
4.262
THR329
3.268
LEU330
2.832
GLY331
3.065
MET332
3.641
PHE357
3.135
THR358
3.952
ALA360
4.167
HIS361
3.314
GLN362
3.022
HIS365
3.385
HIS371
2.800
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| Ligand Name: 2-(4-Chlorophenoxy)-N-{[(4r)-4-Methyl-2,5-Dioxoimidazolidin-4-Yl]methyl}acetamide | Ligand Info | |||||
| Structure Description | Crystal structure of human ADAMTS-4 in complex with inhibitor (compound 1, 2-(4-chlorophenoxy)-N-{[(4R)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl} acetamide) | PDB:4WK7 | ||||
| Method | X-ray diffraction | Resolution | 1.24 Å | Mutation | No | [5] |
| PDB Sequence |
SRFVETLVVA
226 DDKMAAFHGA236 GLKRYLLTVM246 AAAAKAFKHP256 SIRNPVSLVV266 TRLVILGPQV 281 GPSAAQTLRS291 FCAWQRGLNT301 PEDSDPDHFD311 TAILFTRQDL321 CGVSTCDTLG 331 MADVGTVCDP341 ARSCAIVEDD351 GLQSAFTAAH361 ELGHVFNMLH371 DNSKPCISLN 381 GPLSRHVMAP393 VMAHVDPEEP403 WSPCSARFIT413 DFLDNGYGHC423 LLDKPEAPL |
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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) | 38.889 (21/54) | 7.53E-07 |
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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 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 | [+] 1 WikiPathways | + | ||||
| 1 | Endochondral Ossification | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | 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 2 | Aggrecanase inhibitors. US9206139. | |||||
| REF 3 | Synthesis and biological evaluation of biphenylsulfonamide carboxylate aggrecanase-1 inhibitors. Bioorg Med Chem Lett. 2006 Jan 15;16(2):311-6. | |||||
| REF 4 | Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5. Protein Sci. 2008 Jan;17(1):16-21. | |||||
| REF 5 | Identification of potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical and surgical models of osteoarthritis. J Med Chem. 2014 Dec 26;57(24):10476-85. | |||||
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