1. Drug Repositioning and Pharmacophore Identification in the Discovery of Hookworm MIF Inhibitors
- Author
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Jane S. Merkel, Xin Du, Michael Cappello, Jon J. Vermeire, Yoonsang Cho, Richard Bucala, Lin Leng, and Elias Lolis
- Subjects
Ancylostomatoidea ,Drug ,media_common.quotation_subject ,Clinical Biochemistry ,Pharmacology ,Biology ,Crystallography, X-Ray ,Biochemistry ,Article ,Small Molecule Libraries ,Hookworm Infections ,03 medical and health sciences ,0302 clinical medicine ,Furosemide ,Catalytic Domain ,Drug Discovery ,Animals ,Humans ,Diuretics ,Macrophage Migration-Inhibitory Factors ,Molecular Biology ,030304 developmental biology ,media_common ,Ancylostoma ceylanicum ,Meclofenamic Acid ,0303 health sciences ,Binding Sites ,Anti-Inflammatory Agents, Non-Steroidal ,Drug Repositioning ,General Medicine ,biology.organism_classification ,High-Throughput Screening Assays ,3. Good health ,Kinetics ,Drug repositioning ,Symporter ,Immunology ,Meclofenamate Sodium ,Molecular Medicine ,Macrophage migration inhibitory factor ,Pharmacophore ,030217 neurology & neurosurgery - Abstract
Summary 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.
- Published
- 2011
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