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

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Crichlow GV, Cheng KF, Dabideen D, Ochani M, Aljabari B, Pavlov VA, Miller EJ, Lolis E, Al-Abed Y

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

J Biol Chem. 2007 Aug 10;282(32):23089-95. Epub 2007 May 25.

PubMed ID

17526494 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Macrophage migration inhibitory factor	P14174	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
4-HYDROXYBENZALDEHYDE O-(3,3-DIMETHYLBUTANOYL)OXIME	Macrophage migration inhibitory factor	IC 50 (nM)	7000	N/A	N/A	Details
4-HYDROXYBENZALDEHYDE O-(CYCLOHEXYLCARBONYL)OXIME	Macrophage migration inhibitory factor	IC 50 (nM)	1300	N/A	N/A	Details