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| [[Image:2ooz.jpg|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_2ooz| PDB=2ooz | SCENE= }} | | {{STRUCTURE_2ooz| PDB=2ooz | SCENE= }} |
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| '''Macrophage Migration Inhibitory Factor (MIF) Complexed with OXIM6 (an OXIM Derivative Not Containing a Ring in its R-group)'''
| | ===Macrophage Migration Inhibitory Factor (MIF) Complexed with OXIM6 (an OXIM Derivative Not Containing a Ring in its R-group)=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17526494}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17526494 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17526494}} |
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| ==Disease== | | ==Disease== |
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| [[Category: Alternative ligand-binding mode]] | | [[Category: Alternative ligand-binding mode]] |
| [[Category: Isomerase]] | | [[Category: Isomerase]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 11:21:28 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 21:34:09 2008'' |
