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BioAssay: AID 263781

Inhibition of human TrxR

Plasmodium falciparum thioredoxin reductase (PfTrxR: NADPH+Trx(S)2+H+<-->NADP++Trx(SH)2) is a high Mr flavin-dependent TrxR that reduces thioredoxin (Trx) via a CysXXXXCys pair located penultimately to the C-terminal Gly. In this respect, PfTrxR differs significantly from its human counterpart which bears a Cys-Sec redox pair at the same position. PfTrxR is essentially involved in more ..
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 Tested Compounds
 Tested Compounds
All(11)
 
 
Active(2)
 
 
Unspecified(9)
 
 
 Tested Substances
 Tested Substances
All(11)
 
 
Active(2)
 
 
Unspecified(9)
 
 
 Related BioAssays
 Related BioAssays
AID: 263781
Data Source: ChEMBL (347984)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2010-05-24
Modify Date: 2013-11-18

Data Table ( Complete ):           Active    All
Targets
Sequence: RecName: Full=Thioredoxin reductase 1, cytoplasmic; Short=TR; AltName: Full=Gene associated with retinoic and interferon-induced mortality 12 protein; Short=GRIM-12; Short=Gene associated with retinoic and IFN-induced mortality 12 protein; AltName: Full=KM-102-derived reductase-like factor; AltName: Full=Thioredoxin reductase TR1
Description ..   
Protein Family: Pyridine nucleotide-disulphide oxidoreductase, dimerization domain
Comment ..   

Gene:TXNRD1     Related Protein 3D Structures     More BioActivity Data..


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BioActive Compounds: 2
Description:
Title: Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents.

Abstract: Plasmodium falciparum thioredoxin reductase (PfTrxR: NADPH+Trx(S)2+H+<-->NADP++Trx(SH)2) is a high Mr flavin-dependent TrxR that reduces thioredoxin (Trx) via a CysXXXXCys pair located penultimately to the C-terminal Gly. In this respect, PfTrxR differs significantly from its human counterpart which bears a Cys-Sec redox pair at the same position. PfTrxR is essentially involved in antioxidant defense and redox regulation of the parasite and has been previously validated by knock-out studies as a potential drug target for malaria chemotherapy. Moreover, human TrxR is present in most cancer cells at levels tenfold higher than in normal cells. Here we report the discovery of a series of potent inhibitors of PfTrxR. The three most promising inhibitors, 3(IC50(PfTrxR)=2 microM and IC50(hTrxR)=50 microM), 7(IC50(PfTrxR)=2 microM and IC50(hTrxR)=140 microM), and 11(IC50(PfTrxR)=0.5 microM and IC50(hTrxR)=4 microM) were selective for the parasite enzyme. Detailed mechanistic characterization of the effects of these compounds on the PfTrxR-catalyzed reaction showed clear uncompetitive inhibition with respect to both substrate and cofactor. For the most specific PfTrxR inhibitor 7, an alkylation mechanism study based on a thiol conjugation model was performed. Furthermore, all three compounds were active in the lower micromolar range on the chloroquine-resistant P. falciparum strain K1 in vitro.
(PMID: 16458512)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.

Categorized Comment
ChEMBL Assay Type: Binding

ChEMBL Assay Data Source: Scientific Literature

ChEMBL Target ID: 104858

ChEMBL Target Type: Target is a group of closely related proteins

Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1IC50*IC50 PubChem standard valueFloatμM
2BEIBinding Efficiency Index(nM)Float
3SEISurface 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 data validityIC50 data validityString

* Activity Concentration.

Data Table (Concise)
Classification
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