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
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DOI：
10.1074/jbc.m701825200
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发表时间：
2007-08-10
影响因子：
4.8
通讯作者：
Al-Abed, Yousef
中科院分区：
文献类型：
--
作者：
Crichlow, Gregg V.;Cheng, Kai Fan;Al-Abed, Yousef
药效团是化学支架，在其上进行特定位点处的化学部分（R基团）的变化以鉴定R基团的组合，其增加小分子抑制剂的治疗效力，同时使不良反应最小化。我们开发了一种基于羰基肟（OXIM）支架的药效团，用于巨噬细胞迁移抑制因子（MIF），一种参与脓毒症病理学的蛋白质，以验证抑制催化位点可以产生治疗益处。我们研究了基于MIF. OXIM的抑制剂的晶体结构，发现与活性位点结合的两个相反取向依赖于R-基团的化学结构。基于先前对羟基苯丙酮酸和（S，R）-3-（4-羟基苯基）-4，5-二氢-5-异恶唑乙酸甲酯（ISO-1）的研究，一种取向是完全出乎意料的。我们进一步证实，意想不到的结合模式的目标MIF在细胞研究中显示，一种化合物，OXIM-11，消除了反调节活性的MIF抗炎糖皮质激素的作用。在盲肠结扎和穿刺诱导的脓毒症发作后24小时开始的小鼠的OXIM-11治疗与媒介物治疗的对照相比显著改善了存活率，证实了MIF催化位点的抑制可以产生治疗效果。MIF抑制剂复合物的晶体结构为进一步基于结构的药物设计工作提供了见解。
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.