Target Information

Target General Information

Target ID

T69912 (Former ID: TTDC00116)

Target Name

Platelet-activating factor acetylhydrolase (PLA2G7)

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

Target Type

Clinical trial target

[1]

Disease

[+] 3 Target-related Diseases

Alzheimer disease [ICD-11: 8A20]

Arterial occlusive disease [ICD-11: BD40]

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

UniProt ID

PAFA_HUMAN

EC Number

EC 3.1.1.47

Sequence

MVPPKLHVLFCLCGCLAVVYPFDWQYINPVAHMKSSAWVNKIQVLMAAASFGQTKIPRGN
GPYSVGCTDLMFDHTNKGTFLRLYYPSQDNDRLDTLWIPNKEYFWGLSKFLGTHWLMGNI
LRLLFGSMTTPANWNSPLRPGEKYPLVVFSHGLGAFRTLYSAIGIDLASHGFIVAAVEHR
DRSASATYYFKDQSAAEIGDKSWLYLRTLKQEEETHIRNEQVRQRAKECSQALSLILDID
HGKPVKNALDLKFDMEQLKDSIDREKIAVIGHSFGGATVIQTLSEDQRFRCGIALDAWMF
PLGDEVYSRIPQPLFFINSEYFQYPANIIKMKKCYSPDKERKMITIRGSVHQNFADFTFA
TGKIIGHMLKLKGDIDSNVAIDLSNKASLAFLQKHLGLHKDFDQWDCLIEGDDENLIPGT
NINTTNQHIMLQNSSGIEKYN

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3D Structure

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PDB

HIT2.0 ID

T37G49

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

GSK2647544

Drug Info

Phase 1

Alzheimer disease

[2]

Rilapladib

Drug Info

Phase 1

Cardiovascular disease

[3]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

RPAF-AH

Drug Info

Discontinued in Phase 3

Sepsis

[4]

Goxalapladib

Drug Info

Discontinued in Phase 1

Arteriosclerosis

[5]

GSK568859

Drug Info

Discontinued in Phase 1

Arteriosclerosis

[6]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 4 Modulator drugs

GSK2647544

Drug Info

[7]

RPAF-AH

Drug Info

[10]

Goxalapladib

Drug Info

[11]

GSK568859

Drug Info

[7]

Inhibitor

[+] 9 Inhibitor drugs

Rilapladib

Drug Info

[1], [8]

Bicyclic pyrimidine derivative 2

Drug Info

[9]

Indolizine derivative 1

Drug Info

[9]

(1r)-1,2,2-trimethylpropyl (r)-methylphosphinate

Drug Info

[12]

(E)-(thiophen-2-ylmethylidene)amino benzoate

Drug Info

[13]

3,4-difluorobenzaldehyde O-benzoyloxime

Drug Info

[14]

4-fluorobenzaldehyde O-benzoyloxime

Drug Info

[14]

Benzaldehyde O-benzoyloxime

Drug Info

[14]

SB-381320

Drug Info

[13]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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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

[15]

PDB Sequence

KIPRGNGPYS

⁶⁴

VGCTDLMFDH

⁷⁴

TNKGTFLRLY

⁸⁴

YPSQDNDRLD

⁹⁴

TLWIPNKEYF

¹⁰⁴

WGLSKFLGTH

¹¹⁴

WLMGNILRLL

¹²⁴

FGSMTTPANW

¹³⁴

NSPLRPGEKY

¹⁴⁴

PLVVFSHGLG

¹⁵⁴

AFRTLYSAIG

¹⁶⁴

IDLASHGFIV

¹⁷⁴

AAVEHRDRSA

¹⁸⁴

SATYYFKDQS

¹⁹⁴

AAEIGDKSWL

²⁰⁴

YLRTLKQEEE

²¹⁴

THIRNEQVRQ

²²⁴

RAKECSQALS

²³⁴

LILDIDHGKP

²⁴⁴

VKNALDLKFD

²⁵⁴

MEQLKDSIDR

²⁶⁴

EKIAVIGHSF

²⁷⁴

GGATVIQTLS

²⁸⁴

EDQRFRCGIA

²⁹⁴

LDAWMFPLGD

³⁰⁴

EVYSRIPQPL

³¹⁴

FFINSEYFQY

³²⁴

PANIIKMKKC

³³⁴

YSPDKERKMI

³⁴⁴

TIRGSVHQNF

³⁵⁴

ADFTFATGKI

³⁶⁴

IGHMLKLKGD

³⁷⁴

IDSNVAIDLS

³⁸⁴

NKASLAFLQK

³⁹⁴

HLGLHKDFDQ

⁴⁰⁴

WDCLIEGDDE

⁴¹⁴

NLIPGTNINT

⁴²⁴

Residue

Distance (Å)

LEU107

3.335

PHE110

3.340

HIS151

4.853

GLY152

2.866

LEU153

1.820

GLY154

2.510

ALA155

3.210

LEU159

3.200

Residue

Distance (Å)

TYR160

3.057

SER185

4.532

HIS272

3.167

SER273

4.267

HIS351

3.751

GLN352

2.816

ALA355

3.220

PHE357

3.553

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

[16]

PDB Sequence

TKIPRGNGPY

⁶³

SVGCTDLMFD

⁷³

HTNKGTFLRL

⁸³

YYPSQDNDRL

⁹³

DTLWIPNKEY

¹⁰³

FWGLSKFLGT

¹¹³

HWLMGNILRL

¹²³

LFGSMTTPAN

¹³³

WNSPLRPGEK

¹⁴³

YPLVVFSHGL

¹⁵³

GAFRTLYSAI

¹⁶³

GIDLASHGFI

¹⁷³

VAAVEHRDRS

¹⁸³

ASATYYFKDQ

¹⁹³

SAAEIGDKSW

²⁰³

LYLRTLKQEE

²¹³

ETHIRNEQVR

²²³

QRAKECSQAL

²³³

SLILDIDHGK

²⁴³

PVKNALDLKF

²⁵³

DMEQLKDSID

²⁶³

REKIAVIGHS

²⁷³

FGGATVIQTL

²⁸³

SEDQRFRCGI

²⁹³

ALDAWMFPLG

³⁰³

DEVYSRIPQP

³¹³

LFFINSEYFQ

³²³

YPANIIKMKK

³³³

CYSPDKERKM

³⁴³

ITIRGSVHQN

³⁵³

FADFTFATGK

³⁶³

IIGHMLKLKG

³⁷³

DIDSNVAIDL

³⁸³

SNKASLAFLQ

³⁹³

KHLGLHKDFD

⁴⁰³

QWDCLIEGDD

⁴¹³

ENLIPGTNIN

⁴²³

Residue

Distance (Å)

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

Residue

Distance (Å)

SER273

2.751

PHE274

2.816

GLY275

4.856

TRP298

3.327

PHE322

4.296

HIS351

3.516

GLN352

3.354

ALA355

3.869

PHE357

3.171

LEU369

3.456

LYS370

4.753

LEU371

3.461

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
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

Different Human System Profiles of Target

Top

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

There is no similarity protein (E value < 0.005) for this target


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.

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Ether lipid metabolism	hsa00565	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy

Degree	3	Degree centrality	3.22E-04	Betweenness centrality	5.13E-04
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

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Ether lipid metabolism

Metabolic pathways

Biosynthesis of antibiotics

PID Pathway

[+] 1 PID Pathways

Lissencephaly gene (LIS1) in neuronal migration and development

WikiPathways

[+] 2 WikiPathways

IL1 and megakaryotyces in obesity

Synthesis, Secretion, and Deacylation of Ghrelin

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

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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