Target Information
| Target General Information | Top | |||||
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| Target ID |
T08856
(Former ID: TTDR01266)
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| Target Name |
Matrix metalloproteinase-8 (MMP-8)
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| Synonyms |
PMNL-CL; PMNL collagenase; Neutrophil collagenase; CLG1
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| Gene Name |
MMP8
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Rheumatoid arthritis [ICD-11: FA20] | |||||
| Function |
Can degrade fibrillar type I, II, and III collagens.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.24.34
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| Sequence |
MFSLKTLPFLLLLHVQISKAFPVSSKEKNTKTVQDYLEKFYQLPSNQYQSTRKNGTNVIV
EKLKEMQRFFGLNVTGKPNEETLDMMKKPRCGVPDSGGFMLTPGNPKWERTNLTYRIRNY TPQLSEAEVERAIKDAFELWSVASPLIFTRISQGEADINIAFYQRDHGDNSPFDGPNGIL AHAFQPGQGIGGDAHFDAEETWTNTSANYNLFLVAAHEFGHSLGLAHSSDPGALMYPNYA FRETSNYSLPQDDIDGIQAIYGLSSNPIQPTGPSTPKPCDPSLTFDAITTLRGEILFFKD RYFWRRHPQLQRVEMNFISLFWPSLPTGIQAAYEDFDRDLIFLFKGNQYWALSGYDILQG YPKDISNYGFPSSVQAIDAAVFYRSKTYFFVNDQFWRYDNQRQFMEPGYPKSISGAFPGI ESKVDAVFQQEHFFHVFSGPRYYAFDLIAQRVTRVARGNKWLNCRYG Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T69OL5 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | CIPEMASTAT | Drug Info | Phase 3 | Rheumatoid arthritis | [1], [2] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | GM6001 | Drug Info | Discontinued in Phase 2 | Corneal ulcer | [3] | |
| 2 | BB-1101 | Drug Info | Terminated | Multiple sclerosis | [4] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | CIPEMASTAT | Drug Info | [1] | |||
| Inhibitor | [+] 22 Inhibitor drugs | + | ||||
| 1 | GM6001 | Drug Info | [5] | |||
| 2 | BB-1101 | Drug Info | [6] | |||
| 3 | SC-44463 | Drug Info | [7] | |||
| 4 | 1-Hydroxyamine-2-Isobutylmalonic Acid | Drug Info | [8] | |||
| 5 | 2-(biphenyl-4-ylsulfonamido)pentanedioic acid | Drug Info | [9] | |||
| 6 | 2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide | Drug Info | [10] | |||
| 7 | 2-HYDROXYCARBAMOYL-4-METHYL-PENTANOIC ACID | Drug Info | [11] | |||
| 8 | 2-Thiomethyl-3-Phenylpropanoic Acid | Drug Info | [8] | |||
| 9 | 3-(4-Methoxy-benzenesulfonyl)-cyclohexanethiol | Drug Info | [12] | |||
| 10 | 3-(4-Methoxy-benzenesulfonyl)-propane-1-thiol | Drug Info | [12] | |||
| 11 | 3-(4-Phenoxy-benzenesulfonyl)-cyclohexanethiol | Drug Info | [12] | |||
| 12 | 3-(4-Phenoxy-benzenesulfonyl)-propane-1-thiol | Drug Info | [12] | |||
| 13 | 3-AMINO-AZACYCLOTRIDECAN-2-ONE | Drug Info | [11] | |||
| 14 | 4-amino-3-(4-(hexyloxy)phenyl)-4-oxobutanoic acid | Drug Info | [9] | |||
| 15 | Glycinamid | Drug Info | [8] | |||
| 16 | IK-862 | Drug Info | [13] | |||
| 17 | METHYLAMINO-PHENYLALANYL-LEUCYL-HYDROXAMIC ACID | Drug Info | [11] | |||
| 18 | MMI270 | Drug Info | [14] | |||
| 19 | N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide | Drug Info | [10] | |||
| 20 | Ro-37-9790 | Drug Info | [15] | |||
| 21 | SL422 | Drug Info | [16] | |||
| 22 | [2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid | Drug Info | [10] | |||
| 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: Acetohydroxamic acid | Ligand Info | |||||
| Structure Description | Crystal structure of the complex between MMP-8 and a non-zinc chelating inhibitor | PDB:3DPF | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [17] |
| PDB Sequence |
MLTPGNPKWE
89 RTNLTYRIRN99 YTPQLSEAEV109 ERAIKDAFEL119 WSVASPLIFT129 RISQGEADIN 139 IAFYQRDHGD149 NSPFDGPNGI159 LAHAFQPGQG169 IGGDAHFDAE179 ETWTNTSANY 189 NLFLVAAHEF199 GHSLGLAHSS209 DPGALMYPNY219 AFRETSNYSL229 PQDDIDGIQA 239 IYG
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| Ligand Name: Batimastat | Ligand Info | |||||
| Structure Description | COMPLEX OF BB94 WITH THE CATALYTIC DOMAIN OF MATRIX METALLOPROTEINASE-8 | PDB:1MMB | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [18] |
| PDB Sequence |
NPKWERTNLT
94 YRIRNYTPQL104 SEAEVERAIK114 DAFELWSVAS124 PLIFTRISQG134 EADINIAFYQ 144 RDHGDNSPFD154 GPNGILAHAF164 QPGQGIGGDA174 HFDAEETWTN184 TSANYNLFLV 194 AAHEFGHSLG204 LAHSSDPGAL214 MYPNYAFRET224 SNYSLPQDDI234 DGIQAIYG |
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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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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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| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 1.91E-05 |
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| Closeness centrality | 1.86E-01 | Radiality | 1.31E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.85E+01 | Topological coefficient | 5.00E-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 | ||
| 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-regulating microRNAs | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Alzheimer disease-presenilin pathway | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | Collagen degradation | |||||
| 2 | Degradation of the extracellular matrix | |||||
| 3 | Activation of Matrix Metalloproteinases | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Activation of Matrix Metalloproteinases | |||||
| 2 | Matrix Metalloproteinases | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| Target QSAR Model | ||||||
| References | Top | |||||
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| REF 1 | Matrix metalloproteinase inhibition lowers mortality and brain injury in experimental pneumococcal meningitis. Infect Immun. 2014 Apr;82(4):1710-8. | |||||
| 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: 6466). | |||||
| REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001387) | |||||
| REF 4 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006361) | |||||
| REF 5 | Hydroxamate inhibitors of human gelatinase B (92 kDa), Bioorg. Med. Chem. Lett. 5(4):349-352 (1995). | |||||
| REF 6 | New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase inhibitors. J Med Chem. 1999 Nov 18;42(23):4890-908. | |||||
| REF 7 | 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 8 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 9 | Ranking the selectivity of PubChem screening hits by activity-based protein profiling: MMP13 as a case study. Bioorg Med Chem. 2009 Feb 1;17(3):1101-8. | |||||
| REF 10 | Design, synthesis, biological evaluation, and NMR studies of a new series of arylsulfones as selective and potent matrix metalloproteinase-12 inhib... J Med Chem. 2009 Oct 22;52(20):6347-61. | |||||
| REF 11 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 12 | Synthesis and identification of conformationally constrained selective MMP inhibitors. Bioorg Med Chem Lett. 1999 Jul 5;9(13):1757-60. | |||||
| REF 13 | Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structu... J Med Chem. 2002 Nov 7;45(23):4954-7. | |||||
| REF 14 | Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors. J Med Chem. 1999 Nov 4;42(22):4547-62. | |||||
| REF 15 | 11,21-Bisphenyl-19-norpregnane derivatives are selective antiglucocorticoids, Bioorg. Med. Chem. Lett. 7(17):2299-2302 (1997). | |||||
| REF 16 | Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo. J Med Chem. 2001 Aug 2;44(16):2636-60. | |||||
| REF 17 | Extra binding region induced by non-zinc chelating inhibitors into the S1' subsite of matrix metalloproteinase 8 (MMP-8). J Med Chem. 2009 Feb 26;52(4):1040-9. | |||||
| REF 18 | Structure determination and analysis of human neutrophil collagenase complexed with a hydroxamate inhibitor. Biochemistry. 1995 Oct 31;34(43):14012-20. | |||||
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