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

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

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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 Text:

Gregg V Crichlow,Kai Fan Cheng,Darrin Dabideen,Mahendar Ochani,Bayan Aljabari,Valentin A Pavlov,Edmund J Miller,Elias Lolis,Yousef Al-Abed,

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.

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

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

For similar proteins: recombinant proteins research abstracts see: proteins: recombinant proteins research

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

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 23089-95

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 25

MONTH: 05

YEAR: 2007

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

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LANGUAGE: eng

NlmUniqueID: 2985121

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

KEYWORDS: Recombinant Proteins

MESH TERMS: chemistry

Chemical & Substance for Abstract: Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor. Information

Substance Name: Carbon

Registry Number: 7440-44-0

Grant and Affiliation Information for Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor.

AFFILIATION: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Country: United States

AGENCY: United States NCI

GRANT: T32 CA09085

ACRONYM: CA

MEDLINETA: J Biol Chem

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