title: 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 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.
authors.affiliation: Division of Allergy & Infectious Diseases, University of Washington, Seattle, Washington, United States of America.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Crowther
authors.affiliation: Genzyme Corporation, Waltham, Massachusetts, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Booker
authors.affiliation: The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.affiliation: The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Division of Parasitology, New England Biolabs, Ipswich, Massachusetts, United States of America.
authors.forename: Sylvine
authors.initials: S
authors.lastname: Raverdy
authors.affiliation: Division of Parasitology, New England Biolabs, Ipswich, Massachusetts, United States of America.
authors.forename: Jacopo F
authors.initials: JF
authors.lastname: Novelli
authors.affiliation: Division of Allergy & Infectious Diseases, University of Washington, Seattle, Washington, United States of America.
authors.forename: Panqing
authors.initials: P
authors.lastname: He
authors.affiliation: Division of Allergy & Infectious Diseases, University of Washington, Seattle, Washington, United States of America.
authors.forename: Natalie R G
authors.initials: NR
authors.lastname: Dale
authors.affiliation: Genzyme Corporation, Waltham, Massachusetts, United States of America.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Fife
authors.affiliation: Genzyme Corporation, Waltham, Massachusetts, United States of America.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Barker
authors.affiliation: Genzyme Corporation, Waltham, Massachusetts, United States of America.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Kramer
authors.affiliation: Division of Allergy & Infectious Diseases, University of Washington, Seattle, Washington, United States of America.
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.affiliation: Division of Parasitology, New England Biolabs, Ipswich, Massachusetts, United States of America.
authors.forename: Clotilde K S
authors.initials: CK
authors.lastname: Carlow
authors.affiliation: The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Wang
mesh_terms: D000818:Animals; D017178:Brugia malayi / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D005369:Filaricides / Q000302:isolation & purification* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D020128:Inhibitory Concentration 50; D010736:Phosphoglycerate Mutase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D005369:Filaricides; D010736:Phosphoglycerate Mutase