Design, synthesis, and protein crystallography of biaryltriazoles as potent tautomerase inhibitors of macrophage migration inhibitory factor.
Design, synthesis, and protein crystallography of biaryltriazoles as potent tautomerase inhibitors of macrophage migration inhibitory factor.
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DOI：
10.1021/ja512112j
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发表时间：
2015-03-04
影响因子：
15
通讯作者：
Jorgensen, William L.
中科院分区：
文献类型：
--
作者：
Dziedzic, Pawel;Cisneros, Jose A.;Robertson, Michael J.;Hare, Alissa A.;Danford, Nadia E.;Baxter, Richard H. G.;Jorgensen, William L.
优化报告联芳基三唑作为抑制剂的互变异构酶活性的人巨噬细胞迁移抑制因子（MIF），促炎细胞因子与许多炎症性疾病和癌症。采用了有机合成、酶分析、晶体学和包括自由能微扰（FEP）计算在内的建模的综合方法。X射线晶体结构的3a和3b绑定到MIF的报告，并提供了一个基础的建模工作。在结合位点的抑制剂的住宿是惊人的多氢键和芳基-芳基相互作用。额外的建模鼓励追求5-苯氧基喹啉类似物，这导致了非常有效的化合物3s。通过如在3 w、3 z、3aa和3bb中添加与酚羟基相邻的氟原子以加强关键氢键，进一步增强活性。它还表明，化合物的物理性质可以调制的溶剂暴露的取代基的变化。几种化合物可能是已知最有效的MIF互变异构酶抑制剂;最有效的化合物比充分研究的（R）-ISO-1活性高1000倍以上，比色烯-4-酮Orita-13活性高200倍以上。
Optimization is reported for biaryltriazoles as inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with numerous inflammatory diseases and cancer. A combined approach was taken featuring organic synthesis, enzymatic assaying, crystallography, and modeling including free-energy perturbation (FEP) calculations. X-ray crystal structures for 3a and 3b bound to MIF are reported and provided a basis for the modeling efforts. The accommodation of the inhibitors in the binding site is striking with multiple hydrogen bonds and aryl–aryl interactions. Additional modeling encouraged pursuit of 5-phenoxyquinolinyl analogues, which led to the very potent compound 3s. Activity was further enhanced by addition of a fluorine atom adjacent to the phenolic hydroxyl group as in 3w, 3z, 3aa, and 3bb to strengthen a key hydrogen bond. It is also shown that physical properties of the compounds can be modulated by variation of solvent-exposed substituents. Several of the compounds are likely the most potent known MIF tautomerase inhibitors; the most active ones are more than 1000-fold more active than the well-studied (R)-ISO-1 and more than 200-fold more active than the chromen-4-one Orita-13.
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