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Chem Biol. 2011 Sep 23;18(9):1089-101. doi: 10.1016/j.chembiol.2011.07.011.

Drug repositioning and pharmacophore identification in the discovery of hookworm MIF inhibitors.

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1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.

Abstract

The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new pharmacophores. Hookworms are blood-feeding, intestinal nematode parasites that infect up to 600 million people worldwide. Vaccination with recombinant Ancylostoma ceylanicum macrophage migration inhibitory factor (rAceMIF) provided partial protection from disease, thus establishing a "proof-of-concept" for targeting AceMIF to prevent or treat infection. A high-throughput screen (HTS) against rAceMIF identified six AceMIF-specific inhibitors. A nonsteroidal anti-inflammatory drug (NSAID), sodium meclofenamate, could be tested in an animal model to assess the therapeutic efficacy in treating hookworm disease. Furosemide, an FDA-approved diuretic, exhibited submicromolar inhibition of rAceMIF tautomerase activity. Structure-activity relationships of a pharmacophore based on furosemide included one analog that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity.

PMID:
21944748
PMCID:
PMC3294498
DOI:
10.1016/j.chembiol.2011.07.011
[Indexed for MEDLINE]
Free PMC Article

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