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Updated: May 4, 2026
High-throughput Screening and Biosensing with Fluorescent C. elegans Strains
Published on: May 19, 2011
Cofactor-independent phosphoglycerate mutase from nematodes has limited druggability, as revealed by two
Gregory J Crowther1, Michael L Booker2, Min He3
1Division of Allergy & Infectious Diseases, University of Washington, Seattle, Washington, United States of America.
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 µM) 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.
Insights
Cofactor-independent phosphoglycerate mutase (iPGAM) from parasitic worms is a potential drug target, but high-throughput screening revealed limited druggability. This highlights challenges in predicting target suitability for drug discovery.
Area of Science:
- Biochemistry
- Parasitology
- Drug Discovery
Background:
- Cofactor-independent phosphoglycerate mutase (iPGAM) is crucial for nematode survival but absent in humans, making it a potential drug target for diseases like lymphatic filariasis (LF).
- The small, hydrophilic active site of iPGAM raises questions about its druggability, suggesting allosteric inhibition as an alternative approach.
Purpose of the Study:
- To comprehensively assess the druggability of nematode iPGAMs as potential drug targets.
- To identify novel inhibitors for parasitic nematode iPGAMs through high-throughput screening (HTS).
Main Methods:
- Conducted HTS of approximately 220,000 compounds against *C. elegans* iPGAM and 160,000 compounds against *Brugia malayi* iPGAM.
- Utilized a coupled enzyme assay monitoring NADH consumption via absorbance at 340 nm, demonstrating good assay performance (Z'-factor >0.50).
Main Results:
- Identified two novel chemical inhibitors with modest potency (IC50 >10 µM) against *B. malayi* iPGAM.
- The identified inhibitors were singleton hits, lacking a common scaffold, indicating limited initial success in finding potent drug leads.
Conclusions:
- Nematode iPGAMs exhibit low druggability, posing significant challenges for their development as drug targets despite their biological importance.
- This study exemplifies the 'druggability paradox' in target-based drug discovery, where initial druggability assessments are often necessary but difficult to predict without HTS data.
