Target Information

Target General Information

Target ID

T16688 (Former ID: TTDS00466)

Target Name

Diacylglycerol acyltransferase 1 (DGAT1)

Synonyms

Retinol O-fatty-acyltransferase; Diglyceride acyltransferase; Diacylglycerol O-acyltransferase 1; DGAT; Acyl-CoA retinol O-fatty-acyltransferase; ARAT; AGRP1; ACAT-related gene product 1

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Gene Name

DGAT1

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Hyper-lipoproteinaemia [ICD-11: 5C80]

Function

Catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. In contrast to DGAT2 it is not essential for survival. May be involved in VLDL (very low density lipoprotein) assembly. In liver, plays a role in esterifying exogenous fatty acids to glycerol. Functions as the major acyl-CoA retinol acyltransferase (ARAT) in the skin, where it acts to maintain retinoid homeostasis and prevent retinoid toxicity leading to skin and hair disorders.

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BioChemical Class

Acyltransferase

UniProt ID

DGAT1_HUMAN

EC Number

EC 2.3.1.20

Sequence

MGDRGSSRRRRTGSRPSSHGGGGPAAAEEEVRDAAAGPDVGAAGDAPAPAPNKDGDAGVG
SGHWELRCHRLQDSLFSSDSGFSNYRGILNWCVVMLILSNARLFLENLIKYGILVDPIQV
VSLFLKDPYSWPAPCLVIAANVFAVAAFQVEKRLAVGALTEQAGLLLHVANLATILCFPA
AVVLLVESITPVGSLLALMAHTILFLKLFSYRDVNSWCRRARAKAASAGKKASSAAAPHT
VSYPDNLTYRDLYYFLFAPTLCYELNFPRSPRIRKRFLLRRILEMLFFTQLQVGLIQQWM
VPTIQNSMKPFKDMDYSRIIERLLKLAVPNHLIWLIFFYWLFHSCLNAVAELMQFGDREF
YRDWWNSESVTYFWQNWNIPVHKWCIRHFYKPMLRRGSSKWMARTGVFLASAFFHEYLVS
VPLRMFRLWAFTGMMAQIPLAWFVGRFFQGNYGNAAVWLSLIIGQPIAVLMYVHDYYVLN
YEAPAAEA

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3D Structure

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PDB

HIT2.0 ID

T20IHC

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Hesperetin

Drug Info

Approved

High blood cholesterol level

[2]

Clinical Trial Drug(s)

[+] 3 Clinical Trial Drugs

LCQ908

Drug Info

Phase 3

Hepatitis C virus infection

[3], [4]

AZD7687

Drug Info

Phase 1

Diabetic complication

[5], [6]

P-7435

Drug Info

Phase 1

Diabetic complication

[7]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

DS-7250

Drug Info

Discontinued in Phase 1

Diabetic complication

[8]

JTT-553

Drug Info

Discontinued in Phase 1

Obesity

[9]

PF-04620110

Drug Info

Terminated

Type-2 diabetes

[10], [11]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 26 Inhibitor drugs

Hesperetin

Drug Info

[1]

AZD7687

Drug Info

[6]

P-7435

Drug Info

[14]

amidepsines

Drug Info

[13]

Azole derivative 6

Drug Info

[13]

Azole derivative 7

Drug Info

[13]

Benzamide derivative 19

Drug Info

[13]

Carbamide derivative 3

Drug Info

[13]

Lactam derivative 1

Drug Info

[13]

Lactam derivative 2

Drug Info

[13]

Lactam derivative 3

Drug Info

[13]

Lactam derivative 4

Drug Info

[13]

Lactam derivative 5

Drug Info

[13]

PMID25470667-Compound-AZD3988

Drug Info

[13]

PMID25470667-Compound-BAY744113

Drug Info

[13]

PMID25470667-Compound-Figure4-1A

Drug Info

[13]

PMID25470667-Compound-PF-04620110

Drug Info

[13]

Pyrazine carboxamide derivative 1

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 28

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 29

Drug Info

[13]

Pyridine-amide derivative 1

Drug Info

[13]

Pyridine-carboximide derivative 1

Drug Info

[13]

Pyridine-carboximide derivative 2

Drug Info

[13]

T863

Drug Info

[13]

JTT-553

Drug Info

[16]

PF-04620110

Drug Info

[11]

Modulator

[+] 2 Modulator drugs

LCQ908

Drug Info

[12], [13]

DS-7250

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: Oleoyl-CoA

Ligand Info

Structure Description

Human Diacylglycerol Acyltransferase 1 in complex with oleoyl-CoA

PDB:6VP0

Method

Electron microscopy

Resolution

3.10 Å

Mutation

[17]

PDB Sequence

WELRCHRLQD

⁷³

SLFSSDSGFS

⁸³

NYRGILNWCV

⁹³

VMLILSNARL

¹⁰³

FLENLIKYGI

¹¹³

LVDPIQVVSL

¹²³

FLKDPYSWPA

¹³³

PCLVIAANVF

¹⁴³

AVAAFQVEKR

¹⁵³

LAVGALTEQA

¹⁶³

GLLLHVANLA

¹⁷³

TILCFPAAVV

¹⁸³

LLVESITPVG

¹⁹³

SLLALMAHTI

²⁰³

LFLKLFSYRD

²¹³

VNSWCRRARA

²²³

KHTVSYPDNL

²⁴⁷

TYRDLYYFLF

²⁵⁷

APTLCYELNF

²⁶⁷

PRSPRIRKRF

²⁷⁷

LLRRILEMLF

²⁸⁷

FTQLQVGLIQ

²⁹⁷

QWMVPTIQNS

³⁰⁷

MKPFKDMDYS

³¹⁷

RIIERLLKLA

³²⁷

VPNHLIWLIF

³³⁷

FYWLFHSCLN

³⁴⁷

AVAELMQFGD

³⁵⁷

REFYRDWWNS

³⁶⁷

ESVTYFWQNW

³⁷⁷

NIPVHKWCIR

³⁸⁷

HFYKPMLRRG

³⁹⁷

SSKWMARTGV

⁴⁰⁷

FLASAFFHEY

⁴¹⁷

LVSVPLRMFR

⁴²⁷

LWAFTGMMAQ

⁴³⁷

IPLAWFVGRF

⁴⁴⁷

FQGNYGNAAV

⁴⁵⁷

WLSLIIGQPI

⁴⁶⁷

AVLMYVHDYY

⁴⁷⁷

VLNY

Residue

Distance (Å)

MET199

4.281

TRP334

3.516

LEU335

4.384

PHE337

4.208

PHE338

3.339

LEU341

4.233

PHE342

4.147

TRP364

3.973

THR371

3.839

PHE373

3.748

TRP374

2.875

GLN375

3.167

TRP377

2.429

ASN378

4.031

VAL381

4.024

HIS382

2.339

Residue

Distance (Å)

CYS385

4.097

ILE386

3.564

TYR390

3.121

LYS391

3.952

LYS400

3.143

ARG404

3.262

VAL407

4.000

SER411

3.124

ALA412

4.997

PHE414

4.585

HIS415

3.195

LEU418

4.426

MET434

4.326

LEU461

3.703

GLN465

4.021

PRO466

4.125

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: Phosphatidylserine

Ligand Info

Structure Description

Human Diacylglycerol Acyltransferase 1 in complex with oleoyl-CoA

PDB:6VP0

Method

Electron microscopy

Resolution

3.10 Å

Mutation

[17]

PDB Sequence

WELRCHRLQD

⁷³

SLFSSDSGFS

⁸³

NYRGILNWCV

⁹³

VMLILSNARL

¹⁰³

FLENLIKYGI

¹¹³

LVDPIQVVSL

¹²³

FLKDPYSWPA

¹³³

PCLVIAANVF

¹⁴³

AVAAFQVEKR

¹⁵³

LAVGALTEQA

¹⁶³

GLLLHVANLA

¹⁷³

TILCFPAAVV

¹⁸³

LLVESITPVG

¹⁹³

SLLALMAHTI

²⁰³

LFLKLFSYRD

²¹³

VNSWCRRARA

²²³

KHTVSYPDNL

²⁴⁷

TYRDLYYFLF

²⁵⁷

APTLCYELNF

²⁶⁷

PRSPRIRKRF

²⁷⁷

LLRRILEMLF

²⁸⁷

FTQLQVGLIQ

²⁹⁷

QWMVPTIQNS

³⁰⁷

MKPFKDMDYS

³¹⁷

RIIERLLKLA

³²⁷

VPNHLIWLIF

³³⁷

FYWLFHSCLN

³⁴⁷

AVAELMQFGD

³⁵⁷

REFYRDWWNS

³⁶⁷

ESVTYFWQNW

³⁷⁷

NIPVHKWCIR

³⁸⁷

HFYKPMLRRG

³⁹⁷

SSKWMARTGV

⁴⁰⁷

FLASAFFHEY

⁴¹⁷

LVSVPLRMFR

⁴²⁷

LWAFTGMMAQ

⁴³⁷

IPLAWFVGRF

⁴⁴⁷

FQGNYGNAAV

⁴⁵⁷

WLSLIIGQPI

⁴⁶⁷

AVLMYVHDYY

⁴⁷⁷

VLNY

Residue

Distance (Å)

TRP299

3.833

PHE311

4.179

LYS312

4.162

ASP313

3.849

MET314

2.842

ASP315

4.924

TYR316

3.387

ILE319

4.050

ILE320

4.480

LEU323

4.217

LEU324

3.144

LYS325

3.412

ALA327

3.894

Residue

Distance (Å)

VAL328

3.450

LEU428

4.909

TRP429

3.441

THR432

3.058

GLY433

3.942

ALA436

4.070

LEU459

4.110

ILE462

4.360

ILE463

3.488

GLY464

3.912

ILE467

4.740

ALA468

4.238

MET471

3.765

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
Retinol metabolism	hsa00830	Affiliated Target
Class: Metabolism => Metabolism of cofactors and vitamins	Pathway Hierarchy
Fat digestion and absorption	hsa04975	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy

Degree	4	Degree centrality	4.30E-04	Betweenness centrality	4.30E-04
Closeness centrality	1.42E-01	Radiality	1.16E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	2.00E+00	Topological coefficient	3.33E-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 Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

BioCyc

[+] 1 BioCyc Pathways

Triacylglycerol biosynthesis

KEGG Pathway

[+] 4 KEGG Pathways

Glycerolipid metabolism

Retinol metabolism

Metabolic pathways

Fat digestion and absorption

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Retinol Metabolism

Reactome

[+] 2 Reactome Pathways

Acyl chain remodeling of DAG and TAG

Triglyceride Biosynthesis

WikiPathways

[+] 5 WikiPathways

Vitamin A and Carotenoid Metabolism

Statin Pathway

Triacylglyceride Synthesis

Glycerophospholipid biosynthesis

Fatty acid, triacylglycerol, and ketone body metabolism

References

Top

REF 1

In vitro inhibition of diacylglycerol acyltransferase by prenylflavonoids from Sophora flavescens. Planta Med. 2004 Mar;70(3):258-60.

REF 2

Drug information of Hesperetin, 2008. eduDrugs.

REF 3

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: 7830).

REF 4

ClinicalTrials.gov (NCT01514461) A Randomized, Double-blind, Placebo Controlled Study to Assess Efficacy, Safety and Tolerability of LCQ908 in Subjects With Familial Chylomicronemia Syndrome. U.S. National Institutes of Health.

REF 5

REF 6

Clinical pipeline report, company report or official report of AstraZeneca (2011).

REF 7

ClinicalTrials.gov (NCT01764425) Clinical Trial to Study the Safety Tolerability, Pharmacokinetics, Food Effect & Pharmacodynamics of a New Compound P7435 in Healthy, Overweight and/or Obese Subjects. U.S. National Institutes of Health.

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 800035670)

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 800026874)

REF 10

REF 11

Clinical pipeline report, company report or official report of Pfizer (2011).

REF 12

DGAT1 inhibitors as anti-obesity and anti-diabetic agents. Curr Opin Drug Discov Devel. 2010 Jul;13(4):489-96.

REF 13

Acyltransferase inhibitors: a patent review (2010-present).Expert Opin Ther Pat. 2015 Feb;25(2):145-58.

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 800033014)

REF 15

Clinical pipeline report, company report or official report of Daiichi Sankyo.

REF 16

JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 inhibitor, improves glucose metabolism in diet-induced obesity and genetic T2DM mice. J Pharmacol Sci. 2015 Sep;129(1):51-8.

REF 17

Structure and mechanism of human diacylglycerol O-acyltransferase?1. Nature. 2020 May;581(7808):329-332.

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