Target Information

Target General Information

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Target ID

T44282 (Former ID: TTDR01185)

Target Name

Mitochondrial aldehyde dehydrogenase (ALDH2)

Synonyms

Aldehyde dehydrogenase, mitochondrial; ALDM; ALDHI; ALDH-E2; ALDH class 2

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Gene Name

ALDH2

Target Type

Clinical trial target

[1]

Disease

[+] 3 Target-related Diseases

Cerebral ischaemia [ICD-11: 8B1Z]

Cardiovascular disease [ICD-11: BA00-BE2Z]

Unspecific substance use disorder [ICD-11: 6C4Z]

Function

Second enzyme of the major oxidative pathway of alcohol metabolism. Catalyzes the chemical transformation from acetaldehyde to acetic acid. Additionally, functions as a protector against oxidative stress.

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BioChemical Class

Aldehyde/oxo donor oxidoreductase

UniProt ID

ALDH2_HUMAN

EC Number

EC 1.2.1.3

Sequence

MLRAAARFGPRLGRRLLSAAATQAVPAPNQQPEVFCNQIFINNEWHDAVSRKTFPTVNPS
TGEVICQVAEGDKEDVDKAVKAARAAFQLGSPWRRMDASHRGRLLNRLADLIERDRTYLA
ALETLDNGKPYVISYLVDLDMVLKCLRYYAGWADKYHGKTIPIDGDFFSYTRHEPVGVCG
QIIPWNFPLLMQAWKLGPALATGNVVVMKVAEQTPLTALYVANLIKEAGFPPGVVNIVPG
FGPTAGAAIASHEDVDKVAFTGSTEIGRVIQVAAGSSNLKRVTLELGGKSPNIIMSDADM
DWAVEQAHFALFFNQGQCCCAGSRTFVQEDIYDEFVERSVARAKSRVVGNPFDSKTEQGP
QVDETQFKKILGYINTGKQEGAKLLCGGGIAADRGYFIQPTVFGDVQDGMTIAKEEIFGP
VMQILKFKTIEEVVGRANNSTYGLAAAVFTKDLDKANYLSQALQAGTVWVNCYDVFGAQS
PFGGYKMSGSGRELGEYGLQAYTEVKTVTVKVPQKNS

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3D Structure

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PDB

HIT2.0 ID

T32OC4

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 4 Clinical Trial Drugs

ALD-401

Drug Info

Phase 2

Cerebrovascular ischaemia

[2]

ANS-6637

Drug Info

Phase 1

Substance use disorder

[3]

FP-045

Drug Info

Phase 1

Cardiovascular disease

[4]

GS-6637

Drug Info

Phase 1

Substance use disorder

[5]

Mode of Action

[+] 3 Modes of Action

Modulator

[+] 1 Modulator drugs

ALD-401

Drug Info

[1]

Inhibitor

[+] 7 Inhibitor drugs

ANS-6637

Drug Info

[3]

GS-6637

Drug Info

[6], [7]

Daidzin

Drug Info

[8]

crotylaldehyde

Drug Info

[8]

ISOFORMONENTIN

Drug Info

[9]

Nicotinamide-Adenine-Dinucleotide

Drug Info

[8]

prunetin

Drug Info

[9]

Agonist

[+] 1 Agonist drugs

FP-045

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: NADH

Ligand Info

Structure Description

Human mitochondrial aldehyde dehydrogenase complexed with NADH in the presence of Mg2+

PDB:1O02

Method

X-ray diffraction

Resolution

1.90 Å

Mutation

[10]

PDB Sequence

AVPAPNQQPE

¹⁶

VFCNQIFINN

²⁶

EWHDAVSRKT

³⁶

FPTVNPSTGE

⁴⁶

VICQVAEGDK

⁵⁶

EDVDKAVKAA

⁶⁶

RAAFQLGSPW

⁷⁶

RRMDASHRGR

⁸⁶

LLNRLADLIE

⁹⁶

RDRTYLAALE

¹⁰⁶

TLDNGKPYVI

¹¹⁶

SYLVDLDMVL

¹²⁶

KCLRYYAGWA

¹³⁶

DKYHGKTIPI

¹⁴⁶

DGDFFSYTRH

¹⁵⁶

EPVGVCGQII

¹⁶⁶

PWNFPLLMQA

¹⁷⁶

WKLGPALATG

¹⁸⁶

NVVVMKVAEQ

¹⁹⁶

TPLTALYVAN

²⁰⁶

LIKEAGFPPG

²¹⁶

VVNIVPGFGP

²²⁶

TAGAAIASHE

²³⁶

DVDKVAFTGS

²⁴⁶

TEIGRVIQVA

²⁵⁶

AGSSNLKRVT

²⁶⁶

LELGGKSPNI

²⁷⁶

IMSDADMDWA

²⁸⁶

VEQAHFALFF

²⁹⁶

NQGQCCCAGS

³⁰⁶

RTFVQEDIYD

³¹⁶

EFVERSVARA

³²⁶

KSRVVGNPFD

³³⁶

SKTEQGPQVD

³⁴⁶

ETQFKKILGY

³⁵⁶

INTGKQEGAK

³⁶⁶

LLCGGGIAAD

³⁷⁶

RGYFIQPTVF

³⁸⁶

GDVQDGMTIA

³⁹⁶

KEEIFGPVMQ

⁴⁰⁶

ILKFKTIEEV

⁴¹⁶

VGRANNSTYG

⁴²⁶

LAAAVFTKDL

⁴³⁶

DKANYLSQAL

⁴⁴⁶

QAGTVWVNCY

⁴⁵⁶

DVFGAQSPFG

⁴⁶⁶

GYKMSGSGRE

⁴⁷⁶

LGEYGLQAYT

⁴⁸⁶

EVKTVTVKVP

⁴⁹⁶

QKNS

Residue

Distance (Å)

ILE165

3.464

ILE166

2.851

PRO167

3.353

TRP168

2.881

ASN169

3.091

LYS192

2.776

VAL193

4.230

ALA194

3.712

GLU195

2.815

GLN196

3.904

GLY223

4.560

PHE224

4.030

GLY225

3.278

PRO226

3.743

GLY229

3.225

ALA230

3.323

Residue

Distance (Å)

PHE243

3.128

THR244

4.033

GLY245

3.202

SER246

2.766

ILE249

3.338

VAL252

4.082

ILE253

3.691

GLU268

3.475

LEU269

3.197

GLY270

3.932

CYS302

3.463

GLN349

2.904

LYS352

3.932

GLU399

2.683

ILE400

4.928

PHE401

3.580

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

Ligand Name: Nitroglycerin

Ligand Info

Structure Description

Crystal structure of human aldehyde dehydrogenase-2 in complex with nitroglycerin

PDB:4FR8

Method

X-ray diffraction

Resolution

2.20 Å

Mutation

Yes

[11]

PDB Sequence

VPAPNQQPEV

¹⁷

FCNQIFINNE

²⁷

WHDAVSRKTF

³⁷

PTVNPSTGEV

⁴⁷

ICQVAEGDKE

⁵⁷

DVDKAVKAAR

⁶⁷

AAFQLGSPWR

⁷⁷

RMDASHRGRL

⁸⁷

LNRLADLIER

⁹⁷

DRTYLAALET

¹⁰⁷

LDNGKPYVIS

¹¹⁷

YLVDLDMVLK

¹²⁷

CLRYYAGWAD

¹³⁷

KYHGKTIPID

¹⁴⁷

GDFFSYTRHE

¹⁵⁷

PVGVCGQIIP

¹⁶⁷

WNFPLLMQAW

¹⁷⁷

KLGPALATGN

¹⁸⁷

VVVMKVAEQT

¹⁹⁷

PLTALYVANL

²⁰⁷

IKEAGFPPGV

²¹⁷

VNIVPGFGPT

²²⁷

AGAAIASHED

²³⁷

VDKVAFTGST

²⁴⁷

EIGRVIQVAA

²⁵⁷

GSSNLKRVTL

²⁶⁷

QLGGKSPNII

²⁷⁷

MSDADMDWAV

²⁸⁷

EQAHFALFFN

²⁹⁷

QGQSCSAGSR

³⁰⁷

TFVQEDIYDE

³¹⁷

FVERSVARAK

³²⁷

SRVVGNPFDS

³³⁷

KTEQGPQVDE

³⁴⁷

TQFKKILGYI

³⁵⁷

NTGKQEGAKL

³⁶⁷

LCGGGIAADR

³⁷⁷

GYFIQPTVFG

³⁸⁷

DVQDGMTIAK

³⁹⁷

EEIFGPVMQI

⁴⁰⁷

LKFKTIEEVV

⁴¹⁷

GRANNSTYGL

⁴²⁷

AAAVFTKDLD

⁴³⁷

KANYLSQALQ

⁴⁴⁷

AGTVWVNCYD

⁴⁵⁷

VFGAQSPFGG

⁴⁶⁷

YKMSGSGREL

⁴⁷⁷

GEYGLQAYTE

⁴⁸⁷

VKTVTVKVPQ

⁴⁹⁷

KNS

Residue

Distance (Å)

VAL120

4.865

MET124

4.664

ASN169

3.607

PHE170

3.324

LEU173

3.523

MET174

3.551

TRP177

3.597

THR244

4.356

Residue

Distance (Å)

GLN268

2.940

PHE296

3.035

SER301

2.519

CYS302

3.135

SER303

3.671

ASP457

3.418

PHE459

2.876

PHE465

3.758

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
Glycolysis / Gluconeogenesis	hsa00010	Affiliated Target
Class: Metabolism => Carbohydrate metabolism	Pathway Hierarchy
Ascorbate and aldarate metabolism	hsa00053	Affiliated Target
Class: Metabolism => Carbohydrate metabolism	Pathway Hierarchy
Fatty acid degradation	hsa00071	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Valine, leucine and isoleucine degradation	hsa00280	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
Lysine degradation	hsa00310	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
Arginine and proline metabolism	hsa00330	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
Histidine metabolism	hsa00340	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
Tryptophan metabolism	hsa00380	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
beta-Alanine metabolism	hsa00410	Affiliated Target
Class: Metabolism => Metabolism of other amino acids	Pathway Hierarchy
Glycerolipid metabolism	hsa00561	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Pyruvate metabolism	hsa00620	Affiliated Target
Class: Metabolism => Carbohydrate metabolism	Pathway Hierarchy
Pantothenate and CoA biosynthesis	hsa00770	Affiliated Target
Class: Metabolism => Metabolism of cofactors and vitamins	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	10	Degree centrality	1.07E-03	Betweenness centrality	1.84E-03
Closeness centrality	1.92E-01	Radiality	1.33E+01	Clustering coefficient	1.33E-01
Neighborhood connectivity	8.60E+00	Topological coefficient	1.28E-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

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 14 KEGG Pathways	+
1	Glycolysis / Gluconeogenesis
2	Pentose and glucuronate interconversions
3	Ascorbate and aldarate metabolism
4	Fatty acid degradation
5	Valine, leucine and isoleucine degradation
6	Lysine degradation
7	Arginine and proline metabolism
8	Histidine metabolism
9	Tryptophan metabolism
10	beta-Alanine metabolism
11	Glycerolipid metabolism
12	Pyruvate metabolism
13	Metabolic pathways
14	Biosynthesis of antibiotics
Pathwhiz Pathway	[+] 8 Pathwhiz Pathways	+
1	Beta-Alanine Metabolism
2	Ethanol Degradation
3	Histidine Metabolism
4	Valine, Leucine and Isoleucine Degradation
5	Pyruvate Metabolism
6	Oxidation of Branched Chain Fatty Acids
7	Glycine and Serine Metabolism
8	Tryptophan Metabolism
WikiPathways	[+] 4 WikiPathways	+
1	Tryptophan metabolism
2	Fatty Acid Omega Oxidation
3	Phase 1 - Functionalization of compounds
4	Neurotransmitter Clearance In The Synaptic Cleft

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

A novel aldehyde dehydrogenase-3 activator leads to adult salivary stem cell enrichment in vivo. Clin Cancer Res. 2011 Dec 1;17(23):7265-72.

REF 2

ClinicalTrials.gov (NCT01273337) Study of ALD-401 Via Intracarotid Infusion in Ischemic Stroke Subjects. U.S. National Institutes of Health.

REF 3

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

REF 4

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

REF 5

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800040688)

REF 6

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

REF 7

Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery. Nucleic Acids Res. 2012 Jan;40(Database issue):D1128-36.

REF 8

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

REF 9

Structure of daidzin, a naturally occurring anti-alcohol-addiction agent, in complex with human mitochondrial aldehyde dehydrogenase. J Med Chem. 2008 Aug 14;51(15):4482-7.

REF 10

Coenzyme isomerization is integral to catalysis in aldehyde dehydrogenase. Biochemistry. 2003 Jun 17;42(23):7100-9.

REF 11

Vascular bioactivation of nitroglycerin by aldehyde dehydrogenase-2: reaction intermediates revealed by crystallography and mass spectrometry. J Biol Chem. 2012 Nov 2;287(45):38124-34.

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