title: Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor.
abstract: 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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Gregg V
authors.initials: GV
authors.lastname: Crichlow
authors.forename: Kai Fan
authors.initials: KF
authors.lastname: Cheng
authors.forename: Darrin
authors.initials: D
authors.lastname: Dabideen
authors.forename: Mahendar
authors.initials: M
authors.lastname: Ochani
authors.forename: Bayan
authors.initials: B
authors.lastname: Aljabari
authors.forename: Valentin A
authors.initials: VA
authors.lastname: Pavlov
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Miller
authors.forename: Elias
authors.initials: E
authors.lastname: Lolis
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry; D001665:Binding Sites; D002244:Carbon / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008263:Macrophage Migration-Inhibitory Factors / Q000737:chemistry / Q000378:metabolism*; D008956:Models, Chemical; D016328:NF-kappa B / Q000378:metabolism; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: C522772:4-hydroxybenzaldehyde-O-cyclohexanecarbonyloxime; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D010091:Oximes; D011994:Recombinant Proteins; D002244:Carbon