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BioAssay: AID 743230

Biochemical HTS for inhibitors of nematode cofactor-independent phosphoglycerate mutase (iPGM or iPGAM) activity

Cofactor-independent phosphoglycerate mutase from nematodes has limited druggability, as revealed by two high-throughput screens ..more
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 Tested Compounds
 Tested Compounds
All(2)
 
 
Active(2)
 
 
 Tested Substances
 Tested Substances
All(2)
 
 
Active(2)
 
 
 Related BioAssays
 Related BioAssays
AID: 743230
Data Source: Gregory J. Crowther (2012_1)
Depositor Category: Other
BioAssay Version:
Deposit Date: 2013-12-18
Modify Date: 2014-01-24

Data Table ( Complete ):           Active    All
Target
BioActive Compounds: 2
Description:
Cofactor-independent phosphoglycerate mutase from nematodes has limited druggability, as revealed by two high-throughput screens

ABSTRACT - Cofactor-independent phosphoglycerate mutase (iPGAM) is essential for the growth of C. elegans but is absent from humans, suggesting its potential as a drug target in parasitic nematodes such as Brugia malayi, a cause of lymphatic filariasis (LF). iPGAM's active site is small and hydrophilic, implying that it may not be druggable, but another binding site might permit allosteric inhibition. As a comprehensive assessment of iPGAM's druggability, high-throughput screening (HTS) was conducted at two different locations: ~220,000 compounds were tested against the C. elegans iPGAM by Genzyme Corporation, and ~160,000 compounds were screened against the B. malayi iPGAM at the National Center for Drug Screening in Shanghai. iPGAM's catalytic activity was coupled to downstream glycolytic enzymes, resulting in NADH consumption, as monitored by a decline in visible-light absorbance at 340 nm. This assay performed well in both screens (Z'-factor > 0.50) and identified two novel inhibitors that may be useful as chemical probes. However, these compounds have very modest potency against the B. malayi iPGAM (IC50 > 10 microM) and represent isolated singleton hits rather than members of a common scaffold. Thus, despite the other appealing properties of the nematode iPGAMs, their low druggability makes them challenging to pursue as drug targets. This study illustrates a "druggability paradox" of target-based drug discovery: proteins are generally unsuitable for resource-intensive HTS unless they are considered druggable, yet druggability is often difficult to predict in the absence of HTS data.

A biochemical assay is reported for inhibitors of cofactor-independent phosphoglycerate mutase from Brugia malayi.
Protocol
For full details, please see "Cofactor-independent phosphoglycerate mutase from nematodes has limited druggability, as revealed by two high-throughput screens" by Gregory J. Crowther et al., PLoS Neglected Tropical Diseases (in press).
Comment
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1HitsString
2Chemical nameString
3MWInteger
4IC50*FloatμM
5PUBCHEM_CIDInteger

* Activity Concentration.

Data Table (Concise)
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