Target Information

Target General Information

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Target ID

T94309 (Former ID: TTDC00295)

Target Name

Pancreatic triacylglycerol lipase (PNLIP)

Synonyms

Pancreatic lipase; PTL; PL

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Gene Name

PNLIP

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Bacterial infection [ICD-11: 1A00-1C4Z]

Obesity [ICD-11: 5B80-5B81]

Function

Catalyses the following chemical reaction: triacylglycerol + H2O diacylglycerol + a carboxylate. Acts only on an ester-water interface.

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BioChemical Class

Carboxylic ester hydrolase

UniProt ID

LIPP_HUMAN

EC Number

EC 3.1.1.3

Sequence

MLPLWTLSLLLGAVAGKEVCYERLGCFSDDSPWSGITERPLHILPWSPKDVNTRFLLYTN
ENPNNFQEVAADSSSISGSNFKTNRKTRFIIHGFIDKGEENWLANVCKNLFKVESVNCIC
VDWKGGSRTGYTQASQNIRIVGAEVAYFVEFLQSAFGYSPSNVHVIGHSLGAHAAGEAGR
RTNGTIGRITGLDPAEPCFQGTPELVRLDPSDAKFVDVIHTDGAPIVPNLGFGMSQVVGH
LDFFPNGGVEMPGCKKNILSQIVDIDGIWEGTRDFAACNHLRSYKYYTDSIVNPDGFAGF
PCASYNVFTANKCFPCPSGGCPQMGHYADRYPGKTNDVGQKFYLDTGDASNFARWRYKVS
VTLSGKKVTGHILVSLFGNKGNSKQYEIFKGTLKPDSTHSNEFDSDVDVGDLQMVKFIWY
NNVINPTLPRVGASKIIVETNVGKQFNFCSPETVREEVLLTLTPC

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3D Structure

Click to Show 3D Structure of This Target

PDB

HIT2.0 ID

T99W15

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Dalbavancin

Drug Info

Approved

Bacterial infection

[2], [3]

Orlistat

Drug Info

Approved

Obesity

[3], [4], [5], [6]

Clinical Trial Drug(s)

[+] 3 Clinical Trial Drugs

Pancrecarb

Drug Info

NDA filed

Pancreatic malfunction

[7]

Liprotamase

Drug Info

Phase 3

Cystic fibrosis

[8]

MS-1819

Drug Info

Phase 1/2

Exocrine pancreatic insufficiency

[9]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

AZM-131

Drug Info

Terminated

Obesity

[10]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 6 Inhibitor drugs

Dalbavancin

Drug Info

[1], [11]

(Hydroxyethyloxy)Tri(Ethyloxy)Octane

Drug Info

[16]

B-Nonylglucoside

Drug Info

[17]

B-Octylglucoside

Drug Info

[16]

Daio-Orengedokuto (DOT)

Drug Info

[18]

METHOXYUNDECYLPHOSPHINIC ACID

Drug Info

[17]

Modulator

[+] 5 Modulator drugs

Orlistat

Drug Info

[12]

Pancrecarb

Drug Info

[7]

Liprotamase

Drug Info

[13]

MS-1819

Drug Info

[14]

AZM-131

Drug Info

[15]

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: B-Octylglucoside

Ligand Info

Structure Description

THE 2.46 ANGSTROMS RESOLUTION STRUCTURE OF THE PANCREATIC LIPASE COLIPASE COMPLEX INHIBITED BY A C11 ALKYL PHOSPHONATE

PDB:1LPB

Method

X-ray diffraction

Resolution

2.46 Å

Mutation

[19]

PDB Sequence

KEVCYERLGC

¹⁰

FSDDSPWSGI

²⁰

TERPLHILPW

³⁰

SPKDVNTRFL

³⁹

LYTNENPNNF

⁴⁹

QEVAADSSSI

⁵⁹

SGSNFKTNRK

⁶⁹

TRFIIHGFID

⁷⁹

KGEENWLANV

⁸⁹

CKNLFKVESV

⁹⁹

NCICVDWKGG

¹⁰⁹

SRTGYTQASQ

¹¹⁹

NIRIVGAEVA

¹²⁹

YFVEFLQSAF

¹³⁹

GYSPSNVHVI

¹⁴⁹

GHSLGAHAAG

¹⁵⁹

EAGRRTNGTI

¹⁶⁹

GRITGLDPAE

¹⁷⁹

PCFQGTPELV

¹⁸⁹

RLDPSDAKFV

¹⁹⁹

DVIHTDGAPI

²⁰⁹

VPNLGFGMSQ

²¹⁹

VVGHLDFFPN

²²⁹

GGVEMPGCKK

²³⁹

NILSQIVDID

²⁴⁹

GIWEGTRDFA

²⁵⁹

ACNHLRSYKY

²⁶⁹

YTDSIVNPDG

²⁷⁹

FAGFPCASYN

²⁸⁹

VFTANKCFPC

²⁹⁹

PSGGCPQMGH

³⁰⁹

YADRYPGKTN

³¹⁹

DVGQKFYLDT

³²⁹

GDASNFARWR

³³⁹

YKVSVTLSGK

³⁴⁹

KVTGHILVSL

³⁵⁹

FGNKGNSKQY

³⁶⁹

EIFKGTLKPD

³⁷⁹

STHSNEFDSD

³⁸⁹

VDVGDLQMVK

³⁹⁹

FIWYNNVINP

⁴¹⁰

TLPRVGASKI

⁴²⁰

IVETNVGKQF

⁴³⁰

NFCSPETVRE

⁴⁴⁰

EVLLTLTPC

Residue

Distance (Å)

LYS239

3.215

ASP247

2.918

ILE248

3.198

ASP331

2.570

ALA332

3.020

PHE77

4.954

ILE78

3.863

LYS80

2.143

GLU82

4.131

GLU83

3.347

ASN84

3.423

ARG111

3.690

LEU213

4.352

PHE215

3.604

GLU233

4.516

LYS238

3.312

LYS239

4.304

GLN244

4.683

Residue

Distance (Å)

ASP247

4.677

ILE248

2.674

ASP249

2.588

TRP252

3.004

GLU253

2.463

GLY254

4.920

ASP257

3.521

PHE258

2.660

ALA259

2.973

ALA260

4.216

CYS261

4.182

ASN262

4.272

ARG265

2.092

LYS268

1.931

ASP331

3.490

ALA332

3.018

SER333

1.725

PHE335

3.380

Ligand Name: METHOXYUNDECYLPHOSPHINIC ACID

Ligand Info

Structure Description

THE 2.46 ANGSTROMS RESOLUTION STRUCTURE OF THE PANCREATIC LIPASE COLIPASE COMPLEX INHIBITED BY A C11 ALKYL PHOSPHONATE

PDB:1LPB

Method

X-ray diffraction

Resolution

2.46 Å

Mutation

[19]

PDB Sequence

KEVCYERLGC

¹⁰

FSDDSPWSGI

²⁰

TERPLHILPW

³⁰

SPKDVNTRFL

³⁹

LYTNENPNNF

⁴⁹

QEVAADSSSI

⁵⁹

SGSNFKTNRK

⁶⁹

TRFIIHGFID

⁷⁹

KGEENWLANV

⁸⁹

CKNLFKVESV

⁹⁹

NCICVDWKGG

¹⁰⁹

SRTGYTQASQ

¹¹⁹

NIRIVGAEVA

¹²⁹

YFVEFLQSAF

¹³⁹

GYSPSNVHVI

¹⁴⁹

GHSLGAHAAG

¹⁵⁹

EAGRRTNGTI

¹⁶⁹

GRITGLDPAE

¹⁷⁹

PCFQGTPELV

¹⁸⁹

RLDPSDAKFV

¹⁹⁹

DVIHTDGAPI

²⁰⁹

VPNLGFGMSQ

²¹⁹

VVGHLDFFPN

²²⁹

GGVEMPGCKK

²³⁹

NILSQIVDID

²⁴⁹

GIWEGTRDFA

²⁵⁹

ACNHLRSYKY

²⁶⁹

YTDSIVNPDG

²⁷⁹

FAGFPCASYN

²⁸⁹

VFTANKCFPC

²⁹⁹

PSGGCPQMGH

³⁰⁹

YADRYPGKTN

³¹⁹

DVGQKFYLDT

³²⁹

GDASNFARWR

³³⁹

YKVSVTLSGK

³⁴⁹

KVTGHILVSL

³⁵⁹

FGNKGNSKQY

³⁶⁹

EIFKGTLKPD

³⁷⁹

STHSNEFDSD

³⁸⁹

VDVGDLQMVK

³⁹⁹

FIWYNNVINP

⁴¹⁰

TLPRVGASKI

⁴²⁰

IVETNVGKQF

⁴³⁰

NFCSPETVRE

⁴⁴⁰

EVLLTLTPC

Residue

Distance (Å)

GLY76

3.395

PHE77

1.905

TYR114

3.821

HIS151

3.859

SER152

1.603

LEU153

2.198

GLY154

4.436

Residue

Distance (Å)

ALA178

3.393

GLU179

3.948

PRO180

3.825

ILE209

4.344

LEU213

4.065

PHE215

3.502

HIS263

2.331

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
Glycerolipid metabolism	hsa00561	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Pancreatic secretion	hsa04972	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy
Fat digestion and absorption	hsa04975	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy
Vitamin digestion and absorption	hsa04977	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy

Degree	4	Degree centrality	4.30E-04	Betweenness centrality	6.07E-04
Closeness centrality	1.56E-01	Radiality	1.22E+01	Clustering coefficient	1.67E-01
Neighborhood connectivity	3.75E+00	Topological coefficient	3.25E-01	Eccentricity	13
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

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

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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BioCyc

[+] 2 BioCyc Pathways

Triacylglycerol degradation

Retinol biosynthesis

KEGG Pathway

[+] 5 KEGG Pathways

Glycerolipid metabolism

Metabolic pathways

Pancreatic secretion

Fat digestion and absorption

Vitamin digestion and absorption

Reactome

[+] 1 Reactome Pathways

Retinoid metabolism and transport

WikiPathways

[+] 2 WikiPathways

Visual phototransduction

Lipid digestion, mobilization, and transport

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 1

Pfizer. Product Development Pipeline. March 31 2009.

REF 2

2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.

REF 3

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

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 800003007)

REF 5

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: 5277).

REF 6

Obesity and pharmacologic therapy. Endocrinol Metab Clin North Am. 2003 Dec;32(4):1005-24.

REF 7

Clinical pipeline report, company report or official report of Digestive Care.

REF 8

ClinicalTrials.gov (NCT00500084) Phase III ALTU-135 CP Safety Trial. U.S. National Institutes of Health.

REF 9

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030334)

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 800008694)

REF 11

Dalbavancin: a novel once-weekly lipoglycopeptide antibiotic. Clin Infect Dis. 2008 Feb 15;46(4):577-83.

REF 12

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

REF 13

Clinical pipeline report, company report or official report of Anthera Pharmaceuticals.

REF 14

Clinical pipeline report, company report or official report of AzurRx.

REF 15

US patent application no. 7217,697, Glucopyranosyloxypyrazole derivative medicinal composition containing the same medicinal use thereof and intermediate therefor.

REF 16

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 17

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 18

Daio-Orengedokuto inhibits HMG-CoA reductase and pancreatic lipase. Biol Pharm Bull. 2002 Nov;25(11):1442-5.

REF 19

The 2.46 A resolution structure of the pancreatic lipase-colipase complex inhibited by a C11 alkyl phosphonate. Biochemistry. 1995 Mar 7;34(9):2751-62.

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