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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ancylostomatoidea / drug effects
  • Ancylostomatoidea / metabolism*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Diuretics / chemistry
  • Diuretics / pharmacology
  • Diuretics / therapeutic use
  • Drug Repositioning*
  • Furosemide / chemistry
  • Furosemide / pharmacology
  • Furosemide / therapeutic use
  • High-Throughput Screening Assays
  • Hookworm Infections / drug therapy
  • Humans
  • Kinetics
  • Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
  • Macrophage Migration-Inhibitory Factors / genetics
  • Macrophage Migration-Inhibitory Factors / metabolism
  • Meclofenamic Acid / chemistry
  • Meclofenamic Acid / pharmacology
  • Meclofenamic Acid / therapeutic use
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Diuretics
  • Macrophage Migration-Inhibitory Factors
  • Small Molecule Libraries
  • Meclofenamic Acid
  • Furosemide

Associated data

  • PDB/3RF4
  • PDB/3RF5