Target Information

Target General Information

Top

Target ID

T18664 (Former ID: TTDI02646)

Target Name

Monoglyceride lipase (MAGL)

Synonyms

Monoacylglycerol lipase; MGL; Lysophospholipaselike; Lysophospholipase-like; Lysophospholipase homolog; HUK5; HU-K5

Click to Show/Hide

Gene Name

MGLL

Target Type

Clinical trial target

[1]

Disease

[+] 2 Target-related Diseases

General pain disorder [ICD-11: 8E43]

Tic disorder [ICD-11: 8A05]

Function

Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain. Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth. Converts monoacylglycerides to free fatty acids and glycerol.

Click to Show/Hide

BioChemical Class

Carboxylic ester hydrolase

UniProt ID

MGLL_HUMAN

EC Number

EC 3.1.1.23

Sequence

MPEESSPRRTPQSIPYQDLPHLVNADGQYLFCRYWKPTGTPKALIFVSHGAGEHSGRYEE
LARMLMGLDLLVFAHDHVGHGQSEGERMVVSDFHVFVRDVLQHVDSMQKDYPGLPVFLLG
HSMGGAIAILTAAERPGHFAGMVLISPLVLANPESATTFKVLAAKVLNLVLPNLSLGPID
SSVLSRNKTEVDIYNSDPLICRAGLKVCFGIQLLNAVSRVERALPKLTVPFLLLQGSADR
LCDSKGAYLLMELAKSQDKTLKIYEGAYHVLHKELPEVTNSVFHEINMWVSQRTATAGTA
SPP

Click to Show/Hide

3D Structure

Click to Show 3D Structure of This Target

PDB

HIT2.0 ID

T95CAO

Drugs and Modes of Action

Top

Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

ABX-1431

Drug Info

Phase 1

Neuropathic pain

[1]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 39 Inhibitor drugs

ABX-1431

Drug Info

[1]

Azetidine-benzoxazin-3(4H)-one derivative 1

Drug Info

[2]

Azetidine-benzoxazin-3(4H)-one derivative 2

Drug Info

[2]

Azetidinyl-piperazine derivative 1

Drug Info

[2]

Azetidinyl-piperazine derivative 2

Drug Info

[2]

Azetidinyl-piperazine derivative 3

Drug Info

[2]

Azetidinyl-piperidine derivative 1

Drug Info

[2]

Azetidinyl-piperidine derivative 3

Drug Info

[2]

Carbamate derivative 11

Drug Info

[2]

Carbamate derivative 12

Drug Info

[2]

Carbamate derivative 13

Drug Info

[2]

Carbamate derivative 14

Drug Info

[2]

Carbamate derivative 15

Drug Info

[2]

Carbamate derivative 16

Drug Info

[2]

Carbamate derivative 17

Drug Info

[2]

Carbamate derivative 9

Drug Info

[2]

Carbamide derivative 24

Drug Info

[2]

Carbamide derivative 25

Drug Info

[2]

Carbamide derivative 26

Drug Info

[2]

Piperazine carbamic compound 1

Drug Info

[2]

Piperazine carbamic compound 2

Drug Info

[2]

Piperazine carbamic compound 3

Drug Info

[2]

Piperazine carbamic compound 4

Drug Info

[2]

PMID29053063-Compound-11c

Drug Info

[2]

PMID29053063-Compound-11d

Drug Info

[2]

PMID29053063-Compound-15

Drug Info

[2]

PMID29053063-Compound-17

Drug Info

[2]

PMID29053063-Compound-5

Drug Info

[2]

PMID29053063-Compound-7a

Drug Info

[2]

PMID29053063-Compound-7b

Drug Info

[2]

PMID29053063-Compound-7c

Drug Info

[2]

PMID29053063-Compound-7d

Drug Info

[2]

PMID29053063-Compound-7e

Drug Info

[2]

PMID29053063-Compound-7f

Drug Info

[2]

Pyrazole derivative 81

Drug Info

[2]

Pyrazole derivative 82

Drug Info

[2]

Pyrazole derivative 83

Drug Info

[2]

Pyrazole derivative 85

Drug Info

[2]

JZL184

Drug Info

[3]

Cell-based Target Expression Variations

Top

Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

Top

Ligand Name: (2-Cyclohexyl-1,3-Benzoxazol-6-Yl){3-[4-(Pyrimidin-2-Yl)piperazin-1-Yl]azetidin-1-Yl}methanone

Ligand Info

Structure Description

Crystal Structure of a soluble form of human MGLL in complex with an inhibitor

PDB:3PE6

Method

X-ray diffraction

Resolution

1.35 Å

Mutation

Yes

[4]

PDB Sequence

PRRTPQSIPY

¹⁶

QDLPHLVNAD

²⁶

GQYLFCRYWA

³⁶

PTGTPKALIF

⁴⁶

VSHGAGEHSG

⁵⁶

RYEELARMLM

⁶⁶

GLDLLVFAHD

⁷⁶

HVGHGQSEGE

⁸⁶

RMVVSDFHVF

⁹⁶

VRDVLQHVDS

¹⁰⁶

MQKDYPGLPV

¹¹⁶

FLLGHSMGGA

¹²⁶

IAILTAAERP

¹³⁶

GHFAGMVLIS

¹⁴⁶

PLVLANPESA

¹⁵⁶

TTFKVLAAKV

¹⁶⁶

LNSVLPNLSS

¹⁷⁶

GPIDSSVLSR

¹⁸⁶

NKTEVDIYNS

¹⁹⁶

DPLICRAGLK

²⁰⁶

VCFGIQLLNA

²¹⁶

VSRVERALPK

²²⁶

LTVPFLLLQG

²³⁶

SADRLCDSKG

²⁴⁶

AYLLMELAKS

²⁵⁶

QDKTLKIYEG

²⁶⁶

AYHVLHKELP

²⁷⁶

EVTNSVFHEI

²⁸⁶

NMWVSQRTA

Residue

Distance (Å)

GLY50

2.463

ALA51

1.986

GLY52

4.848

GLU53

2.595

ARG57

3.782

TYR58

4.411

HIS121

2.743

SER122

2.178

MET123

2.072

GLY124

4.147

LEU148

2.856

ALA151

2.474

ASN152

4.302

SER155

3.002

ALA156

2.467

PHE159

2.997

LYS160

4.667

ILE179

2.588

ASP180

4.985

Residue

Distance (Å)

SER181

2.587

SER182

4.645

LEU184

2.322

SER185

2.803

ASN187

4.281

GLU190

2.800

VAL191

2.250

TYR194

2.125

LEU205

3.042

GLY210

3.923

LEU213

2.543

LEU214

2.228

VAL217

3.632

LEU241

2.294

CYS242

4.559

HIS269

2.423

VAL270

2.545

HIS272

4.467

LYS273

2.585

Ligand Name: (4R)-1-(2'-chloro[1,1'-biphenyl]-3-yl)-4-[4-(1,3-thiazole-2-carbonyl)piperazin-1-yl]pyrrolidin-2-one

Ligand Info

Structure Description

Crystal structure of human monoacylglycerol lipase in complex with compound 3l

PDB:5ZUN

Method

X-ray diffraction

Resolution

1.35 Å

Mutation

Yes

[5]

PDB Sequence

PRRTPQSIPY

¹⁶

QDLPHLVNAD

²⁶

GQYLFCRYWA

³⁶

PTGTPKALIF

⁴⁶

VSHGAGEHSG

⁵⁶

RYEELARMLM

⁶⁶

GLDLLVFAHD

⁷⁶

HVGHGQSEGE

⁸⁶

RMVVSDFHVF

⁹⁶

VRDVLQHVDS

¹⁰⁶

MQKDYPGLPV

¹¹⁶

FLLGHSMGGA

¹²⁶

IAILTAAERP

¹³⁶

GHFAGMVLIS

¹⁴⁶

PLVLANPESA

¹⁵⁶

TTFKVLAAKV

¹⁶⁶

LNSVLPNLSS

¹⁷⁶

GPIDSSVLSR

¹⁸⁶

NKTEVDIYNS

¹⁹⁶

DPLICRAGLK

²⁰⁶

VCFGIQLLNA

²¹⁶

VSRVERALPK

²²⁶

LTVPFLLLQG

²³⁶

SADRLCDSKG

²⁴⁶

AYLLMELAKS

²⁵⁶

QDKTLKIYEG

²⁶⁶

AYHVLHKELP

²⁷⁶

EVTNSVFHEI

²⁸⁶

NMWVSQRTA

Residue

Distance (Å)

GLY50

3.362

ALA51

2.795

GLU53

3.217

ARG57

2.823

MET88

3.603

HIS121

3.459

SER122

2.879

MET123

2.887

GLY124

4.602

LEU148

4.498

GLY177

3.432

PRO178

3.666

ILE179

3.609

Residue

Distance (Å)

SER181

3.500

LEU184

3.642

SER185

3.580

GLU190

3.675

VAL191

3.699

TYR194

3.413

LEU205

3.653

PHE209

4.262

LEU213

3.771

LEU241

3.590

HIS269

3.995

VAL270

3.684

LYS273

3.673

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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Protein ABHD8 (ABHD8)	PF00561	23.954 (63/263)	3.57E-07
Protein phosphatase methylesterase 1 (PME-1)	PF12697	29.730 (33/111)	1.43E-04
(Lyso)-N-acylphosphatidylethanolamine lipase (ABHD4)	PF00561	23.902 (49/205)	3.00E-03


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
Glycerolipid metabolism	hsa00561	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Thermogenesis	hsa04714	Affiliated Target
Class: Organismal Systems => Environmental adaptation	Pathway Hierarchy
Retrograde endocannabinoid signaling	hsa04723	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Regulation of lipolysis in adipocytes	hsa04923	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.58E-01	Radiality	1.23E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	8.00E+00	Topological coefficient	1.00E+00	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

Top

Drug Property Profile of Target

Top

(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

Co-Targets

Top

Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

Top

Target-regulating microRNAs

Target-regulating microRNAs Info

Target Affiliated Biological Pathways

Top

BioCyc

[+] 1 BioCyc Pathways

Triacylglycerol degradation

KEGG Pathway

[+] 3 KEGG Pathways

Glycerolipid metabolism

Metabolic pathways

Retrograde endocannabinoid signaling

NetPath Pathway

[+] 1 NetPath Pathways

EGFR1 Signaling Pathway

Reactome

[+] 2 Reactome Pathways

Acyl chain remodeling of DAG and TAG

Hormone-sensitive lipase (HSL)-mediated triacylglycerol hydrolysis

WikiPathways

[+] 4 WikiPathways

Lipid digestion, mobilization, and transport

Glycerophospholipid biosynthesis

GPCR downstream signaling

Effects of PIP2 hydrolysis

References

Top

REF 1

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 2

A patent review of Monoacylglycerol Lipase (MAGL) inhibitors (2013-2017).Expert Opin Ther Pat. 2017 Dec;27(12):1341-1351.

REF 3

Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol. 2009 Jan;5(1):37-44.

REF 4

Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 ? resolution. Protein Sci. 2011 Apr;20(4):670-83.

REF 5

Design, Synthesis, and Evaluation of Piperazinyl Pyrrolidin-2-ones as a Novel Series of Reversible Monoacylglycerol Lipase Inhibitors. J Med Chem. 2018 Oct 25;61(20):9205-9217.

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.

Prof. Yuzong CHEN

Prof. Feng ZHU