Target Information

Target General Information

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Target ID

T33124 (Former ID: TTDI02364)

Target Name

D-amino acid oxidase (DAO)

Synonyms

Daminoacid oxidase; DAMOX; DAAO

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Gene Name

DAO

Target Type

Clinical trial target

[1]

Disease

[+] 2 Target-related Diseases

Ataxic disorder [ICD-11: 8A03]

Schizophrenia [ICD-11: 6A20]

Function

Regulates the level of the neuromodulator D-serine in the brain. Has high activity towards D-DOPA and contributes to dopamine synthesis. Could act as a detoxifying agent which removes D-amino acids accumulated during aging. Acts on a variety of D-amino acids with a preference for those having small hydrophobic side chains followed by those bearing polar, aromatic, and basic groups. Does not act on acidic amino acids.

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BioChemical Class

CH-NH(2) donor oxidoreductase

UniProt ID

OXDA_HUMAN

EC Number

EC 1.4.3.3

Sequence

MRVVVIGAGVIGLSTALCIHERYHSVLQPLDIKVYADRFTPLTTTDVAAGLWQPYLSDPN
NPQEADWSQQTFDYLLSHVHSPNAENLGLFLISGYNLFHEAIPDPSWKDTVLGFRKLTPR
ELDMFPDYGYGWFHTSLILEGKNYLQWLTERLTERGVKFFQRKVESFEEVAREGADVIVN
CTGVWAGALQRDPLLQPGRGQIMKVDAPWMKHFILTHDPERGIYNSPYIIPGTQTVTLGG
IFQLGNWSELNNIQDHNTIWEGCCRLEPTLKNARIIGERTGFRPVRPQIRLEREQLRTGP
SNTEVIHNYGHGGYGLTIHWGCALEAAKLFGRILEEKKLSRMPPSHL

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3D Structure

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PDB

HIT2.0 ID

T36HAE

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

TAK-831

Drug Info

Phase 2

Friedreich's ataxia

[2]

TAK-831

Drug Info

Phase 2

Friedreich's ataxia

[3]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

SEP-227900

Drug Info

Terminated

Cognitive impairment

[4]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 3 Inhibitor drugs

TAK-831

Drug Info

[1], [2]

TAK-831

Drug Info

[5]

SEP-227900

Drug Info

[4]

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: Flavin-Adenine Dinucleotide

Ligand Info

Structure Description

Crystal structure of human D-amino acid oxidase in complex with inhibitor

PDB:7U9U

Method

X-ray diffraction

Resolution

1.66 Å

Mutation

[6]

PDB Sequence

MRVVVIGAGV

¹⁰

IGLSTALCIH

²⁰

ERYHSVLQPL

³⁰

DIKVYADRFT

⁴⁰

PLTTTDVAAG

⁵⁰

LWQPYLSDPN

⁶⁰

NPQEADWSQQ

⁷⁰

TFDYLLSHVH

⁸⁰

SPNAENLGLF

⁹⁰

LISGYNLFHE

¹⁰⁰

AIPDPSWKDT

¹¹⁰

VLGFRKLTPR

¹²⁰

ELDMFPDYGY

¹³⁰

GWFHTSLILE

¹⁴⁰

GKNYLQWLTE

¹⁵⁰

RLTERGVKFF

¹⁶⁰

QRKVESFEEV

¹⁷⁰

AREGADVIVN

¹⁸⁰

CTGVWAGALQ

¹⁹⁰

RDPLLQPGRG

²⁰⁰

QIMKVDAPWM

²¹⁰

KHFILTHDPE

²²⁰

RGIYNSPYII

²³⁰

PGTQTVTLGG

²⁴⁰

IFQLGNWSEL

²⁵⁰

NNIQDHNTIW

²⁶⁰

EGCCRLEPTL

²⁷⁰

KNARIIGERT

²⁸⁰

GFRPVRPQIR

²⁹⁰

LEREQLRTGP

³⁰⁰

SNTEVIHNYG

³¹⁰

HGGYGLTIHW

³²⁰

GCALEAAKLF

³³⁰

GRILEEKKLS

³⁴⁰

Residue

Distance (Å)

ILE6

3.197

GLY7

2.104

ALA8

1.929

GLY9

2.374

VAL10

2.842

ILE11

2.222

GLY12

3.289

TYR35

3.826

ALA36

2.525

ASP37

2.086

ARG38

1.801

PHE39

3.831

THR43

2.608

THR44

1.706

THR45

1.842

ASP46

4.673

VAL47

2.265

ALA48

1.825

ALA49

3.270

GLY50

2.183

LEU51

1.970

TRP52

3.858

GLN53

3.960

LEU145

4.558

ARG162

2.440

LYS163

2.791

VAL164

1.956

GLU165

4.144

CYS181

2.912

THR182

2.419

Residue

Distance (Å)

GLY183

2.956

VAL184

4.221

TRP185

2.291

ALA188

3.505

LEU189

2.723

GLY198

4.156

ARG199

4.583

GLY200

2.314

GLN201

3.971

ILE202

2.170

TYR228

3.101

ILE230

4.227

THR237

4.571

ILE241

4.755

THR280

4.703

GLY281

2.520

PHE282

3.439

ARG283

2.500

PRO284

2.629

TYR309

4.327

GLY310

4.563

HIS311

2.744

GLY312

1.779

GLY313

2.399

TYR314

2.446

GLY315

2.192

LEU316

2.613

THR317

1.819

ILE318

4.534

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

Ligand Name: 4H-thieno[3,2-b]pyrrole-5-carboxylic acid

Ligand Info

Structure Description

IN VITRO AND IN VIVO INHIBITION OF HUMAN D-AMINO ACID OXIDASE: REGULATION OF D-SERINE CONCENTRATION IN THE BRAIN

PDB:3ZNN

Method

X-ray diffraction

Resolution

1.90 Å

Mutation

[7]

PDB Sequence

MRVVVIGAGV

¹⁰

IGLSTALCIH

²⁰

ERYHSVLQPL

³⁰

DIKVYADRFT

⁴⁰

PLTTTDVAAG

⁵⁰

LWQPYLSDPN

⁶⁰

NPQEADWSQQ

⁷⁰

TFDYLLSHVH

⁸⁰

SPNAENLGLF

⁹⁰

LISGYNLFHE

¹⁰⁰

AIPDPSWKDT

¹¹⁰

VLGFRKLTPR

¹²⁰

ELDMFPDYGY

¹³⁰

GWFHTSLILE

¹⁴⁰

GKNYLQWLTE

¹⁵⁰

RLTERGVKFF

¹⁶⁰

QRKVESFEEV

¹⁷⁰

AREGADVIVN

¹⁸⁰

CTGVWAGALQ

¹⁹⁰

RDPLLQPGRG

²⁰⁰

QIMKVDAPWM

²¹⁰

KHFILTHDPE

²²⁰

RGIYNSPYII

²³⁰

PGTQTVTLGG

²⁴⁰

IFQLGNWSEL

²⁵⁰

NNIQDHNTIW

²⁶⁰

EGCCRLEPTL

²⁷⁰

KNARIIGERT

²⁸⁰

GFRPVRPQIR

²⁹⁰

LEREQLRTGP

³⁰⁰

SNTEVIHNYG

³¹⁰

HGGYGLTIHW

³²⁰

GCALEAAKLF

³³⁰

GRILEEKKLS

³⁴⁰

Residue

Distance (Å)

LEU51

3.513

TRP52

4.812

GLN53

3.780

LEU215

4.011

TYR224

3.313

TYR228

2.809

Residue

Distance (Å)

ILE230

3.573

ARG283

2.552

GLY313

2.668

TYR314

4.905

THR317

4.554

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

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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 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
Glycine, serine and threonine metabolism	hsa00260	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
Arginine and proline metabolism	hsa00330	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
D-Amino acid metabolism	hsa00470	Affiliated Target
Class: Metabolism => Metabolism of other amino acids	Pathway Hierarchy
Peroxisome	hsa04146	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy

Degree	6	Degree centrality	6.45E-04	Betweenness centrality	5.16E-04
Closeness centrality	1.91E-01	Radiality	1.33E+01	Clustering coefficient	3.33E-01
Neighborhood connectivity	1.48E+01	Topological coefficient	2.96E-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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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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KEGG Pathway

[+] 6 KEGG Pathways

Glycine, serine and threonine metabolism

Arginine and proline metabolism

D-Arginine and D-ornithine metabolism

Metabolic pathways

Biosynthesis of antibiotics

Peroxisome

Pathwhiz Pathway

[+] 2 Pathwhiz Pathways

Arginine and Proline Metabolism

D-Arginine and D-Ornithine Metabolism

WikiPathways

[+] 1 WikiPathways

Metabolism of amino acids and derivatives

References

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REF 1

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

REF 2

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

REF 3

ClinicalTrials.gov (NCT03214588) Efficacy, Tolerability, and Pharmacokinetics of Multiple Doses of Oral TAK-831 in Adults With Friedreich Ataxia. U.S. National Institutes of Health.

REF 4

The Therapeutic Potential of D-Amino Acid Oxidase (DAAO) Inhibitors. Open Med Chem J. 2010; 4: 3-9.

REF 5

Mechanistic Multilayer Quantitative Model for Nonlinear Pharmacokinetics, Target Occupancy and Pharmacodynamics (PK/TO/PD) Relationship of D-Amino Acid Oxidase Inhibitor, TAK-831 in Mice. Pharm Res. 2020 Aug 5;37(8):164.

REF 6

Discovery of a Novel Class of d-Amino Acid Oxidase Inhibitors Using the Schr?dinger Computational Platform. J Med Chem. 2022 May 12;65(9):6775-6802.

REF 7

Structural, kinetic, and pharmacodynamic mechanisms of D-amino acid oxidase inhibition by small molecules. J Med Chem. 2013 May 9;56(9):3710-24.

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