Target Information

Target General Information

Target ID

T36557 (Former ID: TTDC00069)

Target Name

Peroxisome proliferator-activated receptor delta (PPARD)

Synonyms

Peroxisomeproliferator-activated receptor beta; Peroxisomeproliferator activated receptor beta/delta; Peroxisome proliferator-activated receptor beta; PPARdelta; PPARB; PPAR-delta; PPAR-beta; Nuclear receptor subfamily 1 group C member 2; Nuclear hormone receptor 1; NUCI; NUC1; NR1C2

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Gene Name

PPARD

Target Type

Clinical trial target

[1]

Disease

[+] 2 Target-related Diseases

Non-alcoholic fatty liver disease [ICD-11: DB92]

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

Function

Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand. Ligand-activated transcription factor.

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BioChemical Class

Nuclear hormone receptor

UniProt ID

PPARD_HUMAN

Sequence

MEQPQEEAPEVREEEEKEEVAEAEGAPELNGGPQHALPSSSYTDLSRSSSPPSLLDQLQM
GCDGASCGSLNMECRVCGDKASGFHYGVHACEGCKGFFRRTIRMKLEYEKCERSCKIQKK
NRNKCQYCRFQKCLALGMSHNAIRFGRMPEAEKRKLVAGLTANEGSQYNPQVADLKAFSK
HIYNAYLKNFNMTKKKARSILTGKASHTAPFVIHDIETLWQAEKGLVWKQLVNGLPPYKE
ISVHVFYRCQCTTVETVRELTEFAKSIPSFSSLFLNDQVTLLKYGVHEAIFAMLASIVNK
DGLLVANGSGFVTREFLRSLRKPFSDIIEPKFEFAVKFNALELDDSDLALFIAAIILCGD
RPGLMNVPRVEAIQDTILRALEFHLQANHPDAQYLFPKLLQKMADLRQLVTEHAQMMQRI
KKTETETSLHPLLQEIYKDMY

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3D Structure

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AlphaFold

HIT2.0 ID

T74WWP

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 5 Clinical Trial Drugs

GFT-505

Drug Info

Phase 3

Non-alcoholic steatohepatitis

[2]

MBX-8025

Drug Info

Phase 2/3

Obesity

[3]

CER-002

Drug Info

Phase 1

Dyslipidemia

[6]

KD3010

Drug Info

Phase 1

Obesity

[7]

SAR351034

Drug Info

Phase 1

Dyslipidemia

[8]

Discontinued Drug(s)

[+] 4 Discontinued Drugs

GW-501516

Drug Info

Discontinued in Phase 4

Type-1 diabetes

[9], [10]

GSK-677954

Drug Info

Discontinued in Phase 2

Non-alcoholic fatty liver disease

[11]

Indeglitazar

Drug Info

Discontinued in Phase 2

Type-2 diabetes

[12]

Sodelglitazar

Drug Info

Discontinued in Phase 2

Hyperlipidaemia

[13]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

KD-3020

Drug Info

Preclinical

Non-alcoholic fatty liver disease

[11]

Mode of Action

[+] 3 Modes of Action

Modulator

[+] 4 Modulator drugs

GFT-505

Drug Info

[15]

SAR351034

Drug Info

[18]

GW-501516

Drug Info

[1]

SAVX-1

Drug Info

[27]

Agonist

[+] 10 Agonist drugs

MBX-8025

Drug Info

[16]

CER-002

Drug Info

[17]

KD3010

Drug Info

[7]

GSK-677954

Drug Info

[11]

Indeglitazar

Drug Info

[19]

Sodelglitazar

Drug Info

[20]

KD-3020

Drug Info

[11]

DB-900

Drug Info

[21]

GW0742X

Drug Info

[23]

L-783483

Drug Info

[26]

Inhibitor

[+] 5 Inhibitor drugs

GSK-0660

Drug Info

[22]

GSK-3787

Drug Info

[22]

Heptyl-Beta-D-Glucopyranoside

Drug Info

[24]

L-165461

Drug Info

[25]

L-796449

Drug Info

[25]

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: Pemafibrate

Ligand Info

Structure Description

X-ray structure of human PPAR delta ligand binding domain-pemafibrate co-crystals obtained by co-crystallization

PDB:7WGN

Method

X-ray diffraction

Resolution

1.81 Å

Mutation

[28]

PDB Sequence

ADLKAFSKHI

¹⁸²

YNAYLKNFNM

¹⁹²

TKKKARSILT

²⁰²

GKTAPFVIHD

²¹⁵

IETLWQAEKG

²²⁵

LVWGLPPYKE

²⁴⁰

ISVHVFYRCQ

²⁵⁰

CTTVETVREL

²⁶⁰

TEFAKSIPSF

²⁷⁰

SSLFLNDQVT

²⁸⁰

LLKYGVHEAI

²⁹⁰

FAMLASIVNK

³⁰⁰

DGLLVANGSG

³¹⁰

FVTREFLRSL

³²⁰

RKPFSDIIEP

³³⁰

KFEFAVKFNA

³⁴⁰

LELDDSDLAL

³⁵⁰

FIAAIILCGD

³⁶⁰

RPGLMNVPRV

³⁷⁰

EAIQDTILRA

³⁸⁰

LEFHLQANHP

³⁹⁰

DAQYLFPKLL

⁴⁰⁰

QKMADLRQLV

⁴¹⁰

TEHAQMMQRI

⁴²⁰

KKTETETSLH

⁴³⁰

PLLQEIYKDM

⁴⁴⁰

Residue

Distance (Å)

MET192

3.330

ILE213

3.567

LEU219

3.066

GLU223

4.315

TRP228

2.743

HIS244

4.449

VAL245

3.026

PHE246

2.660

ARG248

3.322

CYS249

2.715

GLN250

3.142

THR252

3.314

THR253

2.269

THR256

4.232

HIS287

2.825

ALA289

4.891

ILE290

2.775

Residue

Distance (Å)

PHE291

3.816

MET293

3.224

LEU294

3.060

ILE297

3.111

LEU303

3.044

LEU304

4.331

VAL305

3.616

VAL312

3.642

LEU317

3.295

ILE327

2.827

ILE328

3.017

LYS331

3.441

HIS413

2.564

MET417

2.832

LEU429

4.901

LEU433

3.416

TYR437

2.436

Ligand Name: Bezafibrate

Ligand Info

Structure Description

X-ray structure of human PPAR delta ligand binding domain-bezafibrate co-crystals obtained by co-crystallization

PDB:7WGL

Method

X-ray diffraction

Resolution

2.09 Å

Mutation

[28]

PDB Sequence

DLKAFSKHIY

¹⁸³

NAYLKNFNMT

¹⁹³

KKKARSILTG

²⁰³

KAPFVIHDIE

²¹⁷

TLWQAEKGLV

²²⁷

WLPPYKEISV

²⁴³

HVFYRCQCTT

²⁵³

VETVRELTEF

²⁶³

AKSIPSFSSL

²⁷³

FLNDQVTLLK

²⁸³

YGVHEAIFAM

²⁹³

LASIVNKDGL

³⁰³

LVANGSGFVT

³¹³

REFLRSLRKP

³²³

FSDIIEPKFE

³³³

FAVKFNALEL

³⁴³

DDSDLALFIA

³⁵³

AIILCGDRPG

³⁶³

LMNVPRVEAI

³⁷³

QDTILRALEF

³⁸³

HLQANHPDAQ

³⁹³

YLFPKLLQKM

⁴⁰³

ADLRQLVTEH

⁴¹³

AQMMQRIKKT

⁴²³

ETETSLHPLL

⁴³³

QEIYKDM

Residue

Distance (Å)

TRP228

3.738

VAL245

3.711

PHE246

2.967

ARG248

3.248

CYS249

3.038

GLN250

2.815

THR252

2.591

THR253

2.415

HIS287

2.801

ILE290

4.134

PHE291

3.211

LEU294

3.249

Residue

Distance (Å)

LEU303

3.759

VAL305

3.936

VAL312

4.075

LEU317

3.707

ILE327

3.944

ILE328

3.261

LYS331

4.047

HIS413

2.486

MET417

2.557

LEU429

4.150

LEU433

3.070

TYR437

2.517

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 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 Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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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 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 Pathway Affiliation

Biological Network Descriptors

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

KEGG Pathway	Pathway ID	Affiliated Target
PPAR signaling pathway	hsa03320	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Wnt signaling pathway	hsa04310	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy

Degree	3	Degree centrality	3.22E-04	Betweenness centrality	2.68E-06
Closeness centrality	2.17E-01	Radiality	1.38E+01	Clustering coefficient	3.33E-01
Neighborhood connectivity	4.57E+01	Topological coefficient	4.05E-01	Eccentricity	11
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

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 Regulators

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Target-interacting Proteins

Target-interacting Proteins 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

[+] 4 KEGG Pathways

PPAR signaling pathway

Wnt signaling pathway

Pathways in cancer

Acute myeloid leukemia

NetPath Pathway

[+] 1 NetPath Pathways

IL2 Signaling Pathway

Panther Pathway

[+] 1 Panther Pathways

Wnt signaling pathway

PID Pathway

[+] 2 PID Pathways

Presenilin action in Notch and Wnt signaling

RXR and RAR heterodimerization with other nuclear receptor

Reactome

[+] 3 Reactome Pathways

Import of palmitoyl-CoA into the mitochondrial matrix

Regulation of pyruvate dehydrogenase (PDH) complex

Nuclear Receptor transcription pathway

WikiPathways

[+] 8 WikiPathways

Wnt Signaling Pathway and Pluripotency

Nuclear Receptors in Lipid Metabolism and Toxicity

NRF2 pathway

Nuclear Receptors Meta-Pathway

Vitamin D Receptor Pathway

Ectoderm Differentiation

Adipogenesis

Nuclear Receptors

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Lipid effects of peroxisome proliferator-activated receptor- agonist GW501516 in subjects with low high-density lipoprotein cholesterol: characteristics of metabolic syndrome.Arterioscler Thromb Vasc Biol.2012 Sep;32(9):2289-94.

REF 2

ClinicalTrials.gov (NCT02704403) Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis (NASH) (RESOLVE-IT). 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 800024671)

REF 4

ClinicalTrials.gov (NCT04251182) A Randomized, Double-Blind, Placebo-Controlled Multi-Center Study to Evaluate the Safety and Efficacy of Three Dose Strengths of T3D-959 in Subjects With Mild-to-Moderate Alzheimer's Disease. U.S.National Institutes of Health.

REF 5

ClinicalTrials.gov (NCT02560753) Feasibility Study in Subjects With Mild to Moderate Alzheimer's Disease.

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 800028321)

REF 7

Kalypsys nearing completion of phase Ia study of KD3010 for metabolic disorders. Kalypsys. 2007.

REF 8

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029833)

REF 9

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: 2687).

REF 10

ClinicalTrials.gov (NCT00841217) Regulation of Lipoprotein Transport in Metabolic Syndrome. U.S. National Institutes of Health.

REF 11

Emerging drugs for non-alcoholic fatty liver disease. Expert Opin Emerg Drugs. 2008 Mar;13(1):145-58.

REF 12

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022483)

REF 13

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018093)

REF 14

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026847)

REF 15

Dual peroxisome proliferator-activated receptor / agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects.Diabetes Care.2013 Oct;36(10):2923-30.

REF 16

ClinicalTrials.gov (NCT00701883) Safety and Benefit of MBX-8025 With and Without Commonly Used Statins in Moderately Overweight Patients With High Cholesterol. U. S. National Institute of Health. 2008.

REF 17

Fibrates, glitazones, and peroxisome proliferator-activated receptors. Arterioscler Thromb Vasc Biol. 2010 May; 30(5): 894-899.

REF 18

Addressing Unmet Medical Needs in Type 2 Diabetes: A Narrative Review of Drugs under Development. Curr Diabetes Rev. 2015 March; 11(1): 17-31.

REF 19

Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent. Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):262-7.

REF 20

Docking and molecular dynamics simulations of peroxisome proliferator activated receptors interacting with pan agonist sodelglitazar. Protein Pept Lett. 2011 Oct;18(10):1021-7.

REF 21

CN patent application no. 102459215, 3-(4-aminophenyl)-2-furancarboxylic acid derivative and pharmaceutically acceptable salt thereof.

REF 22

Identification and characterization of 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a selective and irreversibl... J Med Chem. 2010 Feb 25;53(4):1857-61.

REF 23

Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity. Bioorg Med Chem Lett. 2003 May 5;13(9):1517-21.

REF 24

DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.

REF 25

Phenylacetic acid derivatives as hPPAR agonists. Bioorg Med Chem Lett. 2003 Apr 7;13(7):1277-80.

REF 26

Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem. 1999 Mar 5;274(10):6718-25.

REF 27

REF 28

Functional and Structural Insights into Human PPARAlpha/Delta/Gamma Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate. Int J Mol Sci. 2022 Apr 25;23(9):4726.

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