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BioAssay: AID 440720

Inhibition of Mycobacterium tuberculosis phosphorylated DevR binding to fdxA promoter DNA added after DevR phosphorylation by EMSA

Antitubercular treatment is directed against actively replicating organisms. There is an urgent need to develop drugs targeting persistent subpopulations of Mycobacterium tuberculosis. The DevR response regulator is believed to play a key role in bacterial dormancy adaptation during hypoxia. We developed a homology-based model of DevR and used it for the rational design of inhibitors. A more ..
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 Tested Compounds
 Tested Compounds
All(1)
 
 
Active(1)
 
 
 Tested Substances
 Tested Substances
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Active(1)
 
 
 Related BioAssays
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AID: 440720
Data Source: ChEMBL (591898)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2010-07-08
Modify Date: 2013-11-16

Data Table ( Complete ):           Active    All
Target
Sequence: RecName: Full=Transcriptional regulatory protein DevR (DosR)
Description ..   
Protein Family: REC
Comment ..   

Related Protein 3D Structures     More BioActivity Data..
BioActive Compound: 1
Description:
Title: Structure-based design of DevR inhibitor active against nonreplicating Mycobacterium tuberculosis.

Abstract: Antitubercular treatment is directed against actively replicating organisms. There is an urgent need to develop drugs targeting persistent subpopulations of Mycobacterium tuberculosis. The DevR response regulator is believed to play a key role in bacterial dormancy adaptation during hypoxia. We developed a homology-based model of DevR and used it for the rational design of inhibitors. A phenylcoumarin derivative (compound 10) identified by in silico pharmacophore-based screening of 2.5 million compounds employing protocols with some novel features including a water-based pharmacophore query, was characterized further. Compound 10 inhibited DevR binding to target DNA, down-regulated dormancy genes transcription, and drastically reduced survival of hypoxic but not nutrient-starved dormant bacteria or actively growing organisms. Our findings suggest that compound 10 "locks" DevR in an inactive conformation that is unable to bind cognate DNA and induce the dormancy regulon. These results provide proof-of-concept for DevR as a novel target to develop molecules with sterilizing activity against tubercle bacilli.
(PMID: 19827833)
Categorized Comment
ChEMBL Assay Type: Binding

ChEMBL Assay Data Source: Scientific Literature

ChEMBL Target ID: 102872

ChEMBL Target Type: Target is a single protein chain

Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Activity activity commentActivity activity commentString
2Activity standard flagActivity standard flagInteger
3Activity qualifierActivity qualifierString
4Activity published valueActivity published valueFloat
5Activity standard valueActivity standard valueFloat

Data Table (Concise)
Classification
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