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J. Biol. Chem., Vol. 282, Issue 32, 23089-23095, August 10, 2007

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Alternative Chemical Modifications Reverse the Binding Orientation of a Pharmacophore Scaffold in the Active Site of Macrophage Migration Inhibitory Factor^*

Gregg V. Crichlow¹, Kai Fan Cheng¹, Darrin Dabideen, Mahendar Ochani^¶, Bayan Aljabari, Valentin A. Pavlov^¶, Edmund J. Miller^||, Elias Lolis², and Yousef Al-Abed³

From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520 and the Laboratory of Medicinal Chemistry, the ^¶Laboratory of Biomedical Sciences, and the ^||Laboratory of Cardiopulmonary Research, The Feinstein Institute for Medical Research, Manhasset, New York 11030

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.

Received for publication, March 2, 2007 , and in revised form, April 23, 2007.

^* This research was supported by National Institutes of Health Grants HL081655 (to E. J. M. and Y. A.-A.) and AI065029 (to E. L.) and by National Institutes of Health Training Grant T32 CA09085 (to G. V. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 2OOH, 2OOW, and 2OOZ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ The authors have contributed equally to the work.

² To whom correspondence may be addressed. Dept. of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520. Tel.: 203-785-6233; Fax: 203-737-2027; E-mail: elias.lolis{at}yale.edu. ³ To whom correspondence should be addressed: Laboratory of Medicinal Chemistry, Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY 11030. Tel.: 516-562-3406; Fax: 516-562-1022; E-mail: yalabed{at}nshs.edu.

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