Target Information

Target General Information

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Target ID

T30803 (Former ID: TTDI00816)

Target Name

Glutathione reductase (GR)

Synonyms

Glutathione reductase, mitochondrial; GRase; GRD1; GLUR

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Gene Name

GSR

Target Type

Patented-recorded target

[1]

Disease

[+] 1 Target-related Diseases

Breast cancer [ICD-11: 2C60-2C6Y]

Function

Maintains high levels of reduced glutathione in the cytosol.

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BioChemical Class

Sulfur donor oxidoreductase

UniProt ID

GSHR_HUMAN

EC Number

EC 1.8.1.7

Sequence

MALLPRALSAGAGPSWRRAARAFRGFLLLLPEPAALTRALSRAMACRQEPQPQGPPPAAG
AVASYDYLVIGGGSGGLASARRAAELGARAAVVESHKLGGTCVNVGCVPKKVMWNTAVHS
EFMHDHADYGFPSCEGKFNWRVIKEKRDAYVSRLNAIYQNNLTKSHIEIIRGHAAFTSDP
KPTIEVSGKKYTAPHILIATGGMPSTPHESQIPGASLGITSDGFFQLEELPGRSVIVGAG
YIAVEMAGILSALGSKTSLMIRHDKVLRSFDSMISTNCTEELENAGVEVLKFSQVKEVKK
TLSGLEVSMVTAVPGRLPVMTMIPDVDCLLWAIGRVPNTKDLSLNKLGIQTDDKGHIIVD
EFQNTNVKGIYAVGDVCGKALLTPVAIAAGRKLAHRLFEYKEDSKLDYNNIPTVVFSHPP
IGTVGLTEDEAIHKYGIENVKTYSTSFTPMYHAVTKRKTKCVMKMVCANKEEKVVGIHMQ
GLGCDEMLQGFAVAVKMGATKADFDNTVAIHPTSSEELVTLR

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3D Structure

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PDB

ADReCS ID

BADD_A03234 ; BADD_A04357 ; BADD_A05639 ; BADD_A06020

HIT2.0 ID

T23RXU

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: Glutathione

Ligand Info

Structure Description

Catalytic cycle of human glutathione reductase near 1 A resolution

PDB:3DK8

Method

X-ray diffraction

Resolution

1.10 Å

Mutation

[8]

PDB Sequence

AVASYDYLVI

²⁶

GGGSGGLASA

³⁶

RRAAELGARA

⁴⁶

AVVESHKLGG

⁵⁶

TCVNVGCVPK

⁶⁶

KVMWNTAVHS

⁷⁶

EFMHDHADYG

⁸⁶

FPSCEGKFNW

⁹⁶

RVIKEKRDAY

¹⁰⁶

VSRLNAIYQN

¹¹⁶

NLTKSHIEII

¹²⁶

RGHAAFTSDP

¹³⁶

KPTIEVSGKK

¹⁴⁶

YTAPHILIAT

¹⁵⁶

GGMPSTPHES

¹⁶⁶

QIPGASLGIT

¹⁷⁶

SDGFFQLEEL

¹⁸⁶

PGRSVIVGAG

¹⁹⁶

YIAVEMAGIL

²⁰⁶

SALGSKTSLM

²¹⁶

IRHDKVLRSF

²²⁶

DSMISTNCTE

²³⁶

ELENAGVEVL

²⁴⁶

KFSQVKEVKK

²⁵⁶

TLSGLEVSMV

²⁶⁶

TAVPGRLPVM

²⁷⁶

TMIPDVDCLL

²⁸⁶

WAIGRVPNTK

²⁹⁶

DLSLNKLGIQ

³⁰⁶

TDDKGHIIVD

³¹⁶

EFQNTNVKGI

³²⁶

YAVGDVCGKA

³³⁶

LLTPVAIAAG

³⁴⁶

RKLAHRLFEY

³⁵⁶

KEDSKLDYNN

³⁶⁶

IPTVVFSHPP

³⁷⁶

IGTVGLTEDE

³⁸⁶

AIHKYGIENV

³⁹⁶

KTYSTSFTPM

⁴⁰⁶

YHAVTKRKTK

⁴¹⁶

CVMKMVCANK

⁴²⁶

EEKVVGIHMQ

⁴³⁶

GLGCDEMLQG

⁴⁴⁶

FAVAVKMGAT

⁴⁵⁶

KADFDNTVAI

⁴⁶⁶

HPTSSEELVT

⁴⁷⁶

Residue

Distance (Å)

GLY29

4.536

SER30

2.999

LEU33

3.942

ALA34

3.704

ARG37

2.997

GLY55

4.806

CYS58

2.028

VAL59

3.606

Residue

Distance (Å)

VAL64

3.556

TYR106

4.061

LEU110

4.977

TYR114

3.123

THR339

3.284

ILE343

3.342

ARG347

2.885

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Ligand Name: Flavin-Adenine Dinucleotide

Ligand Info

Structure Description

Catalytic cycle of human glutathione reductase near 1 A resolution

PDB:3DK9

Method

X-ray diffraction

Resolution

0.95 Å

Mutation

[8]

PDB Sequence

AVASYDYLVI

²⁶

GGGSGGLASA

³⁶

RRAAELGARA

⁴⁶

AVVESHKLGG

⁵⁶

TCVNVGCVPK

⁶⁶

KVMWNTAVHS

⁷⁶

EFMHDHADYG

⁸⁶

FPSCEGKFNW

⁹⁶

RVIKEKRDAY

¹⁰⁶

VSRLNAIYQN

¹¹⁶

NLTKSHIEII

¹²⁶

RGHAAFTSDP

¹³⁶

KPTIEVSGKK

¹⁴⁶

YTAPHILIAT

¹⁵⁶

GGMPSTPHES

¹⁶⁶

QIPGASLGIT

¹⁷⁶

SDGFFQLEEL

¹⁸⁶

PGRSVIVGAG

¹⁹⁶

YIAVEMAGIL

²⁰⁶

SALGSKTSLM

²¹⁶

IRHDKVLRSF

²²⁶

DSMISTNCTE

²³⁶

ELENAGVEVL

²⁴⁶

KFSQVKEVKK

²⁵⁶

TLSGLEVSMV

²⁶⁶

TAVPGRLPVM

²⁷⁶

TMIPDVDCLL

²⁸⁶

WAIGRVPNTK

²⁹⁶

DLSLNKLGIQ

³⁰⁶

TDDKGHIIVD

³¹⁶

EFQNTNVKGI

³²⁶

YAVGDVCGKA

³³⁶

LLTPVAIAAG

³⁴⁶

RKLAHRLFEY

³⁵⁶

KEDSKLDYNN

³⁶⁶

IPTVVFSHPP

³⁷⁶

IGTVGLTEDE

³⁸⁶

AIHKYGIENV

³⁹⁶

KTYSTSFTPM

⁴⁰⁶

YHAVTKRKTK

⁴¹⁶

CVMKMVCANK

⁴²⁶

EEKVVGIHMQ

⁴³⁶

GLGCDEMLQG

⁴⁴⁶

FAVAVKMGAT

⁴⁵⁶

KADFDNTVAI

⁴⁶⁶

HPTSSEELVT

⁴⁷⁶

Residue

Distance (Å)

ILE26

3.753

GLY27

3.254

GLY28

4.052

GLY29

3.315

SER30

3.250

GLY31

2.836

GLY32

4.159

VAL49

3.708

GLU50

2.658

SER51

3.174

HIS52

3.794

LYS53

3.666

GLY55

4.134

GLY56

3.214

THR57

2.789

CYS58

3.362

VAL61

3.733

GLY62

3.635

CYS63

3.261

LYS66

2.736

GLY128

3.361

HIS129

3.261

ALA130

3.010

Residue

Distance (Å)

ALA155

3.315

THR156

3.401

GLY157

3.364

GLY158

4.391

SER177

3.808

PHE181

4.248

TYR197

3.109

ILE198

3.981

GLU201

4.621

MET202

3.939

ARG291

3.385

ASN294

3.534

LEU298

3.616

VAL329

4.270

GLY330

3.385

ASP331

2.801

VAL332

4.507

LEU337

3.290

LEU338

3.144

THR339

2.943

PRO340

3.097

ALA342

3.955

PHE372

4.291

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

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
Glutathione metabolism	hsa00480	Affiliated Target
Class: Metabolism => Metabolism of other amino acids	Pathway Hierarchy
Thyroid hormone synthesis	hsa04918	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy

Degree	8	Degree centrality	8.59E-04	Betweenness centrality	4.38E-04
Closeness centrality	1.92E-01	Radiality	1.33E+01	Clustering coefficient	3.57E-02
Neighborhood connectivity	7.13E+00	Topological coefficient	1.72E-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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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 Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target Affiliated Biological Pathways

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BioCyc

[+] 2 BioCyc Pathways

Glutathione redox reactions II

Glutathione redox reactions I

KEGG Pathway

[+] 2 KEGG Pathways

Glutathione metabolism

Thyroid hormone synthesis

Pathwhiz Pathway

[+] 2 Pathwhiz Pathways

Glutamate Metabolism

Glutathione Metabolism

WikiPathways

[+] 7 WikiPathways

Metapathway biotransformation

Sulfation Biotransformation Reaction

Oxidative Stress

NRF2 pathway

Nuclear Receptors Meta-Pathway

Selenium Micronutrient Network

Glutathione metabolism

References

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REF 1

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

REF 2

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

REF 3

Thioredoxin reductase inhibitors: a patent review.Expert Opin Ther Pat. 2017 May;27(5):547-556.

REF 4

Irreversible inactivation of trypanothione reductase by unsaturated Mannich bases: a divinyl ketone as key intermediate. J Med Chem. 2005 Nov 17;48(23):7400-10.

REF 5

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

REF 6

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. (Target id: 2613).

REF 7

In vitro inhibition of human erythrocyte glutathione reductase by some new organic nitrates. Bioorg Med Chem Lett. 2009 Jul 1;19(13):3661-3.

REF 8

Catalytic cycle of human glutathione reductase near 1 A resolution. J Mol Biol. 2008 Oct 3;382(2):371-84.

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