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Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor.

Abstract
Pharmacophores are chemical scaffolds upon which changes in chemical moieties (R-groups) at specific sites are made to identify a combination of R-groups that increases the therapeutic potency of a small molecule inhibitor while minimizing adverse effects. We developed a pharmacophore based on a carbonyloxime (OXIM) scaffold for macrophage migration inhibitory factor (MIF), a protein involved in the pathology of sepsis, to validate that inhibition of a catalytic site could produce therapeutic benefits. We studied the crystal structures of MIF.OXIM-based inhibitors and found two opposite orientations for binding to the active site that were dependent on the chemical structures of an R-group. One orientation was completely unexpected based on previous studies with hydroxyphenylpyruvate and (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1). We further confirmed that the unexpected binding mode targets MIF in cellular studies by showing that one compound, OXIM-11, abolished the counter-regulatory activity of MIF on anti-inflammatory glucocorticoid action. OXIM-11 treatment of mice, initiated 24 h after the onset of cecal ligation and puncture-induced sepsis, significantly improved survival when compared with vehicle-treated controls, confirming that inhibition of the MIF catalytic site could produce therapeutic effects. The crystal structures of the MIF inhibitor complexes provide insight for further structure-based drug design efforts.
AuthorsGregg V Crichlow, Kai Fan Cheng, Darrin Dabideen, Mahendar Ochani, Bayan Aljabari, Valentin A Pavlov, Edmund J Miller, Elias Lolis, Yousef Al-Abed
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 32 Pg. 23089-95 (Aug 10 2007) ISSN: 0021-9258 [Print] United States
PMID17526494 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • 4-hydroxybenzaldehyde-O-cyclohexanecarbonyloxime
  • Anti-Inflammatory Agents
  • Glucocorticoids
  • Macrophage Migration-Inhibitory Factors
  • NF-kappa B
  • Oximes
  • Recombinant Proteins
  • Carbon
Topics
  • Anti-Inflammatory Agents (chemistry)
  • Binding Sites
  • Carbon (chemistry)
  • Chemistry, Pharmaceutical (methods)
  • Crystallography, X-Ray (methods)
  • Drug Design
  • Glucocorticoids (metabolism)
  • Humans
  • Leukocytes, Mononuclear (cytology)
  • Macrophage Migration-Inhibitory Factors (chemistry, metabolism)
  • Models, Chemical
  • NF-kappa B (metabolism)
  • Oximes (chemistry, pharmacology)
  • Protein Binding
  • Recombinant Proteins (chemistry)

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