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BioAssay: AID 580672

Inhibition of human glutathione reductase by spectrophotometer

The cancer chemopreventive agent ellagic acid (EA) is a known inhibitor of glutathione S-transferases (GSTs) and possesses antiplasmodial activities in the upper-nanomolar range. In the recent drug development approach, the properties of the active site of Plasmodium falciparum GST were exploited for inhibitor design by introducing one or two additional hydroxyl groups into EA, yielding more ..
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 Tested Compounds
 Tested Compounds
All(3)
 
 
Active(3)
 
 
 Tested Substances
 Tested Substances
All(3)
 
 
Active(3)
 
 
AID: 580672
Data Source: ChEMBL (729212)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2011-09-18
Modify Date: 2014-08-25

Data Table ( Complete ):           View Active Data    View All Data
Target
Sequence: RecName: Full=Glutathione reductase, mitochondrial; Short=GR; Short=GRase; Flags: Precursor
Description ..   
Protein Family: Pyridine nucleotide-disulphide oxidoreductase, dimerization domain
Comment ..   

Gene:GSR     Related Protein 3D Structures     More BioActivity Data..
BioActive Compounds: 3
Description:
Title: Compounds structurally related to ellagic acid show improved antiplasmodial activity.

Abstract: The cancer chemopreventive agent ellagic acid (EA) is a known inhibitor of glutathione S-transferases (GSTs) and possesses antiplasmodial activities in the upper-nanomolar range. In the recent drug development approach, the properties of the active site of Plasmodium falciparum GST were exploited for inhibitor design by introducing one or two additional hydroxyl groups into EA, yielding flavellagic acid (FEA) and coruleoellagic acid (CEA), respectively. Indeed, the inhibition of P. falciparum GST was improved with the increasing hydrophilicity of the planar polyaromatic ring system. Studying the effects of the two compounds on the central redox enzymes of Plasmodium revealed that glutathione reductase and thioredoxin reductase also are inhibited in the lower-micromolar range. Both compounds had strong antiplasmodial activity in the lower-nanomolar range and were particularly effective against chloroquine (CQ)-resistant P. falciparum strains. Neither FEA nor CEA showed cytotoxic effects on human cells. This was supported by negligible changes in transcript levels and enzyme activities of redox enzymes in human A549 cells upon treatment with the compounds. In Plasmodium, however, CEA treatment resulted in a marked downregulation of most antioxidant genes studied and impaired mainly the trophozoite stage of the parasites. In addition, EA, CEA, and FEA were found to strongly inhibit in vitro heme aggregation. In vitro and preliminary in vivo studies indicated that, compared to CQ, CEA is a slowly acting compound and is able to significantly improve the survival of Plasmodium berghei-infected mice. We conclude that FEA and CEA are promising antimalarial compounds that deserve to be studied further.
(PMID: 19015351)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.

Categorized Comment - additional comments and annotations
From BioAssay Depositor:
Assay Type: Binding
Target Type: Target is a single protein chain
Assay Data Source: Scientific Literature
Protein Target Class: enzyme reductase
Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1IC50*IC50 PubChem standard valueFloatμM
3BEIBinding Efficiency Index(nM)Float
2SEISurface Efficiency Index(nM)Float
4LELigand EfficiencyFloat
5LLELipophilic Ligand EfficiencyFloat
6IC50 activity commentIC50 activity commentString
7IC50 standard flagIC50 standard flagInteger
8IC50 qualifierIC50 qualifierString
9IC50 published valueIC50 published valueFloatμM
10IC50 standard valueIC50 standard valueFloatnM
11IC50 binding domainsIC50 binding domainsString

* Activity Concentration.

Data Table (Concise)
Data Table ( Complete ):     View Active Data    View All Data
Classification
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