Drug repositioning and pharmacophore identification in the discovery of hookworm MIF inhibitors.
Chem Biol
; 18(9): 1089-101, 2011 Sep 23.
Article
em En
| MEDLINE
| ID: mdl-21944748
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ancylostomatoidea
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Fatores Inibidores da Migração de Macrófagos
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Reposicionamento de Medicamentos
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article