Coumarin and chromen-4-one analogues as tautomerase inhibitors of macrophage migration inhibitory factor: Discovery and X-ray crystallography
Coumarin and chromen-4-one analogues as tautomerase inhibitors of macrophage migration inhibitory factor: Discovery and X-ray crystallography
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DOI：
10.1021/jm000386o
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发表时间：
2001-02-15
影响因子：
7.3
通讯作者：
Tanaka, A
中科院分区：
文献类型：
--
作者：
Orita, M;Yamamoto, S;Tanaka, A
巨噬细胞移动抑制因子（MIF）是从T细胞和巨噬细胞释放的促炎细胞因子。尽管对MIF的生物学功能的详细了解尚未阐明，但已知MIF催化非生理分子D-多巴色素的互变异构。使用基于结构的计算机辅助搜索的两个数据库的商业可用的化合物，我们已经发现了14个新的互变异构酶抑制剂的MIF，其Ki值的范围为0.038-7.4 μ M。我们还确定了与命中化合物1复合的MIF的晶体结构。结果表明，目标化合物位于MIF的活性位点，其N端脯氨酸在互变异构酶反应中起重要作用，并与MIF形成多个氢键，发生疏水作用。晶体学研究还表明，在MIF活性位点的边缘处存在由Pro-33、Tyr-36、Trp-108和Phe-113组成的疏水表面，并且分子模拟研究表明，几种更有效的命中化合物具有可以与该疏水表面相互作用的芳环。据我们所知，我们的化合物是最有效的MIF互变异构酶抑制剂。这些小的药物样分子之一已与MIF共结晶，并结合到互变异构酶活性的活性位点。分子模型也表明，其他命中化合物可以以类似的方式结合。
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine released from T-cells and macrophages. Although a detailed understanding of the biological functions of MIF has not yet been clarified, it is known that MIF catalyzes the tautomerization of a nonphysiological molecule, D-dopachrome. Using a structure-based computer-assisted search of two databases of commercially available compounds, we have found 14 novel tautomerase inhibitors of MIF whose K-i values are in the range of 0.038-7.4 muM. We also have determined the crystal structure of MIF complexed with the hit compound 1. It showed that the hit compound is located in the active site of MIF containing the N-terminal proline which plays an important role in the tautomerase reaction and forms several hydrogen bonds and undergoes hydrophobic interactions. A crystallographic study also revealed that there is a hydrophobic surface which consists of Pro-33, Tyr-36, Trp-108, and Phe-113 at the rim of the active site of MIF, and molecular modeling studies indicated that several more potent hit compounds have the aromatic rings which can interact with this hydrophobic surface. To our knowledge, our compounds are the most potent tautomerase inhibitors of MIF. One of these small, drug-like molecules has been cocrystallized with MIF and binds to the active site for tautomerase activity. Molecular modeling also suggests that the other hit compounds can bind in a similar fashion.