2oow
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MIF Bound to a Fluorinated OXIM Derivative
OverviewOverview
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 24h after the onset of cecal, ligation and puncture-induced sepsis, significantly improved survival, compared to 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.
About this StructureAbout this Structure
2OOW is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Active as Phenylpyruvate tautomerase, with EC number 5.3.2.1 Full crystallographic information is available from OCA.
ReferenceReference
Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of MIF., Crichlow GV, Cheng KF, Dabideen D, Ochani M, Aljabari B, Pavlov VA, Miller EJ, Lolis E, Al-Abed Y, J Biol Chem. 2007 May 25;. PMID:17526494
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