Target Information
Target General Information | Top | |||||
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Target ID |
T69912
(Former ID: TTDC00116)
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Target Name |
Platelet-activating factor acetylhydrolase (PLA2G7)
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Synonyms |
gVIIA-PLA2; PAFAH; PAF acetylhydrolase; PAF 2-acylhydrolase; Lipoprotein-associated phospholipase A2; LDL-associated phospholipase A2; LDL-PLA(2); Group-VIIA phospholipase A2; 2-acetyl-1-alkylglycerophosphocholine esterase; 1-alkyl-2-acetylglycerophosphocholine esterase
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Gene Name |
PLA2G7
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Alzheimer disease [ICD-11: 8A20] | |||||
2 | Arterial occlusive disease [ICD-11: BD40] | |||||
3 | Cardiovascular disease [ICD-11: BA00-BE2Z] | |||||
Function |
Has a specificity for substrates with a short residue at the sn-2 position. It is inactive against long-chain phospholipids. Modulates the action of platelet-activating factor (PAF) by hydrolyzing the sn-2 ester bond to yield the biologically inactive lyso-PAF.
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BioChemical Class |
Carboxylic ester hydrolase
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UniProt ID | ||||||
EC Number |
EC 3.1.1.47
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Sequence |
MVPPKLHVLFCLCGCLAVVYPFDWQYINPVAHMKSSAWVNKIQVLMAAASFGQTKIPRGN
GPYSVGCTDLMFDHTNKGTFLRLYYPSQDNDRLDTLWIPNKEYFWGLSKFLGTHWLMGNI LRLLFGSMTTPANWNSPLRPGEKYPLVVFSHGLGAFRTLYSAIGIDLASHGFIVAAVEHR DRSASATYYFKDQSAAEIGDKSWLYLRTLKQEEETHIRNEQVRQRAKECSQALSLILDID HGKPVKNALDLKFDMEQLKDSIDREKIAVIGHSFGGATVIQTLSEDQRFRCGIALDAWMF PLGDEVYSRIPQPLFFINSEYFQYPANIIKMKKCYSPDKERKMITIRGSVHQNFADFTFA TGKIIGHMLKLKGDIDSNVAIDLSNKASLAFLQKHLGLHKDFDQWDCLIEGDDENLIPGT NINTTNQHIMLQNSSGIEKYN Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T37G49 |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | GSK2647544 | Drug Info | Phase 1 | Alzheimer disease | [2] | |
2 | Rilapladib | Drug Info | Phase 1 | Cardiovascular disease | [3] | |
Discontinued Drug(s) | [+] 3 Discontinued Drugs | + | ||||
1 | RPAF-AH | Drug Info | Discontinued in Phase 3 | Sepsis | [4] | |
2 | Goxalapladib | Drug Info | Discontinued in Phase 1 | Arteriosclerosis | [5] | |
3 | GSK568859 | Drug Info | Discontinued in Phase 1 | Arteriosclerosis | [6] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Modulator | [+] 4 Modulator drugs | + | ||||
1 | GSK2647544 | Drug Info | [7] | |||
2 | RPAF-AH | Drug Info | [10] | |||
3 | Goxalapladib | Drug Info | [11] | |||
4 | GSK568859 | Drug Info | [7] | |||
Inhibitor | [+] 9 Inhibitor drugs | + | ||||
1 | Rilapladib | Drug Info | [1], [8] | |||
2 | Bicyclic pyrimidine derivative 2 | Drug Info | [9] | |||
3 | Indolizine derivative 1 | Drug Info | [9] | |||
4 | (1r)-1,2,2-trimethylpropyl (r)-methylphosphinate | Drug Info | [12] | |||
5 | (E)-(thiophen-2-ylmethylidene)amino benzoate | Drug Info | [13] | |||
6 | 3,4-difluorobenzaldehyde O-benzoyloxime | Drug Info | [14] | |||
7 | 4-fluorobenzaldehyde O-benzoyloxime | Drug Info | [14] | |||
8 | Benzaldehyde O-benzoyloxime | Drug Info | [14] | |||
9 | SB-381320 | Drug Info | [13] |
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: Benzenesulfonamide | Ligand Info | |||||
Structure Description | Compound binding to Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)discovered through fragment screening | PDB:5JAD | ||||
Method | X-ray diffraction | Resolution | 2.05 Å | Mutation | No | [15] |
PDB Sequence |
KIPRGNGPYS
64 VGCTDLMFDH74 TNKGTFLRLY84 YPSQDNDRLD94 TLWIPNKEYF104 WGLSKFLGTH 114 WLMGNILRLL124 FGSMTTPANW134 NSPLRPGEKY144 PLVVFSHGLG154 AFRTLYSAIG 164 IDLASHGFIV174 AAVEHRDRSA184 SATYYFKDQS194 AAEIGDKSWL204 YLRTLKQEEE 214 THIRNEQVRQ224 RAKECSQALS234 LILDIDHGKP244 VKNALDLKFD254 MEQLKDSIDR 264 EKIAVIGHSF274 GGATVIQTLS284 EDQRFRCGIA294 LDAWMFPLGD304 EVYSRIPQPL 314 FFINSEYFQY324 PANIIKMKKC334 YSPDKERKMI344 TIRGSVHQNF354 ADFTFATGKI 364 IGHMLKLKGD374 IDSNVAIDLS384 NKASLAFLQK394 HLGLHKDFDQ404 WDCLIEGDDE 414 NLIPGTNINT424 T
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Ligand Name: Darapladib | Ligand Info | |||||
Structure Description | Crystal structure of LP_PLA2 in complex with Darapladib | PDB:5I9I | ||||
Method | X-ray diffraction | Resolution | 2.70 Å | Mutation | No | [16] |
PDB Sequence |
TKIPRGNGPY
63 SVGCTDLMFD73 HTNKGTFLRL83 YYPSQDNDRL93 DTLWIPNKEY103 FWGLSKFLGT 113 HWLMGNILRL123 LFGSMTTPAN133 WNSPLRPGEK143 YPLVVFSHGL153 GAFRTLYSAI 163 GIDLASHGFI173 VAAVEHRDRS183 ASATYYFKDQ193 SAAEIGDKSW203 LYLRTLKQEE 213 ETHIRNEQVR223 QRAKECSQAL233 SLILDIDHGK243 PVKNALDLKF253 DMEQLKDSID 263 REKIAVIGHS273 FGGATVIQTL283 SEDQRFRCGI293 ALDAWMFPLG303 DEVYSRIPQP 313 LFFINSEYFQ323 YPANIIKMKK333 CYSPDKERKM343 ITIRGSVHQN353 FADFTFATGK 363 IIGHMLKLKG373 DIDSNVAIDL383 SNKASLAFLQ393 KHLGLHKDFD403 QWDCLIEGDD 413 ENLIPGTNIN423 T
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LEU107
3.249
PHE110
3.554
LEU111
3.357
LEU121
3.189
PHE125
4.211
GLY152
3.528
LEU153
2.631
GLY154
3.021
ALA155
3.945
LEU159
3.259
TYR160
3.687
HIS272
3.958
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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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Ether lipid metabolism | hsa00565 | Affiliated Target |
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Class: Metabolism => Lipid metabolism | Pathway Hierarchy |
Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 5.13E-04 |
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Closeness centrality | 1.70E-01 | Radiality | 1.27E+01 | Clustering coefficient | 0.00E+00 |
Neighborhood connectivity | 9.33E+00 | Topological coefficient | 3.33E-01 | 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 |
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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KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
1 | Ether lipid metabolism | |||||
2 | Metabolic pathways | |||||
3 | Biosynthesis of antibiotics | |||||
PID Pathway | [+] 1 PID Pathways | + | ||||
1 | Lissencephaly gene (LIS1) in neuronal migration and development | |||||
WikiPathways | [+] 2 WikiPathways | + | ||||
1 | IL1 and megakaryotyces in obesity | |||||
2 | Synthesis, Secretion, and Deacylation of Ghrelin |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | Phospholipase A2 inhibitors. Curr Opin Lipidol. 2009 Aug;20(4):327-32. | |||||
REF 2 | ClinicalTrials.gov (NCT01924858) A Positron Emission Tomography (PET) Study to Investigate the Brain Biodistribution of 18F GSK2647544 in Healthy Subjects to Determine Its Ability to Cross the Blood-brain-barrier.. U.S. National Institutes of Health. | |||||
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 800018454) | |||||
REF 4 | ClinicalTrials.gov (NCT00037687) Safety and Efficacy of Recombinant Human Platelet-Activating Factor Acetylhydrolase for the Treatment of Severe Sepsis. 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 800020582) | |||||
REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025982) | |||||
REF 7 | 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: 1432). | |||||
REF 8 | THERAPEUTICS: Rilapladib | |||||
REF 9 | Inhibitors of phospholipase A2 and their therapeutic potential: an update on patents (2012-2016).Expert Opin Ther Pat. 2017 Feb;27(2):217-225. | |||||
REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006777) | |||||
REF 11 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020582) | |||||
REF 12 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
REF 13 | (E)-Phenyl- and -heteroaryl-substituted O-benzoyl-(or acyl)oximes as lipoprotein-associated phospholipase A2 inhibitors. Bioorg Med Chem Lett. 2005 Mar 1;15(5):1525-7. | |||||
REF 14 | Potent inhibitors of lipoprotein-associated phospholipase A(2): benzaldehyde O-heterocycle-4-carbonyloxime. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5576-9. | |||||
REF 15 | Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening. J Med Chem. 2016 Jun 9;59(11):5356-67. | |||||
REF 16 | Structural and Thermodynamic Characterization of Protein-Ligand Interactions Formed between Lipoprotein-Associated Phospholipase A2 and Inhibitors. J Med Chem. 2016 May 26;59(10):5115-20. |
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