2oow: Difference between revisions
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==Overview== | ==Overview== | ||
Pharmacophores are chemical scaffolds upon which changes in chemical | 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. | ||
==Disease== | ==Disease== | ||
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==Reference== | ==Reference== | ||
Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of | Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor., Crichlow GV, Cheng KF, Dabideen D, Ochani M, Aljabari B, Pavlov VA, Miller EJ, Lolis E, Al-Abed Y, J Biol Chem. 2007 Aug 10;282(32):23089-95. Epub 2007 May 25. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17526494 17526494] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Phenylpyruvate tautomerase]] | [[Category: Phenylpyruvate tautomerase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Al-Abed, Y.]] | [[Category: Al-Abed, Y.]] | ||
[[Category: Crichlow, G | [[Category: Crichlow, G V.]] | ||
[[Category: Lolis, E.]] | [[Category: Lolis, E.]] | ||
[[Category: GOL]] | [[Category: GOL]] | ||
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[[Category: isomerase]] | [[Category: isomerase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:20:52 2008'' | ||
Revision as of 16:20, 21 February 2008
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MIF Bound to a Fluorinated OXIM Derivative
Overview
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.
Disease
Known diseases associated with this structure: Persistent Mullerian duct syndrome, type I OMIM:[600957], Rheumatoid arthritis, systemic juvenile, susceptibility to OMIM:[153620]
About this Structure
2OOW is a Single protein structure of sequence from Homo sapiens with SO4, OX4, GOL and IPA as ligands. Active as Phenylpyruvate tautomerase, with EC number 5.3.2.1 Known structural/functional Sites: AC1, AC2, AC3, AC4, AC5, AC6, AC7, AC8, AC9, BC1, BC2, BC3, BC4, BC5, BC6 and BC7. Full crystallographic information is available from OCA.
Reference
Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor., Crichlow GV, Cheng KF, Dabideen D, Ochani M, Aljabari B, Pavlov VA, Miller EJ, Lolis E, Al-Abed Y, J Biol Chem. 2007 Aug 10;282(32):23089-95. Epub 2007 May 25. PMID:17526494
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