A target-based high throughput screen yields Trypanosoma brucei hexokinase small molecule inhibitors with antiparasitic activity.

Abstract:

BACKGROUND:The parasitic protozoan Trypanosoma brucei utilizes glycolysis exclusively for ATP production during infection of the mammalian host. The first step in this metabolic pathway is mediated by hexokinase (TbHK), an enzyme essential to the parasite that transfers the gamma-phospho of ATP to a hexose. Here we describe the identification and confirmation of novel small molecule inhibitors of bacterially expressed TbHK1, one of two TbHKs expressed by T. brucei, using a high throughput screening assay. METHODOLOGY/PRINCIPAL FINDINGS:Exploiting optimized high throughput screening assay procedures, we interrogated 220,233 unique compounds and identified 239 active compounds from which ten small molecules were further characterized. Computation chemical cluster analyses indicated that six compounds were structurally related while the remaining four compounds were classified as unrelated or singletons. All ten compounds were approximately 20-17,000-fold more potent than lonidamine, a previously identified TbHK1 inhibitor. Seven compounds inhibited T. brucei blood stage form parasite growth (0.03

journal_name

PLoS Negl Trop Dis

authors

Sharlow ER,Lyda TA,Dodson HC,Mustata G,Morris MT,Leimgruber SS,Lee KH,Kashiwada Y,Close D,Lazo JS,Morris JC

doi

10.1371/journal.pntd.0000659

subject

Has Abstract

pub_date

2010-04-13 00:00:00

pages

e659

issue

4

eissn

1935-2727

issn

1935-2735

journal_volume

4

pub_type

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