Structure based development of phenylimidazole-derived inhibitors of indoleamine 2,3-dioxygenase.
Structure based development of phenylimidazole-derived inhibitors of indoleamine 2,3-dioxygenase.
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DOI：
10.1021/jm800512z
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发表时间：
2008-08-28
影响因子：
7.3
通讯作者：
Muller AJ
中科院分区：
文献类型：
--
作者：
Kumar S;Jaller D;Patel B;LaLonde JM;DuHadaway JB;Malachowski WP;Prendergast GC;Muller AJ
吲哚胺2，3-双加氧酶（IDO）是治疗癌症、慢性病毒感染和以病理性免疫抑制为特征的其他疾病的重要新靶点。为了开发更有效的IDO抑制剂，对4-苯基咪唑（4-PI）衍生物进行了系统的研究。计算对接实验指导4-PI类似物的设计和合成工作。特别地，研究了4-PI类似物与IDO的三种相互作用：活性位点入口、活性位点内部和血红素铁结合。三种最有效的抑制剂（1、17和18）似乎利用了与活性位点内部的C129和S167的相互作用。所有这三种抑制剂的效力都比4-PI强约10倍。该研究代表了酶抑制剂开发的第一个例子，最近报道了IDO的晶体结构，并为寻找更有效的抑制剂提供了重要的经验教训。
Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. With the goal of developing more potent IDO inhibitors, a systematic study of 4-phenyl-imidazole (4-PI) derivatives was undertaken. Computational docking experiments guided design and synthesis efforts with analogs of 4-PI. In particular, three interactions of 4-PI analogs with IDO were studied: the active site entrance, the interior of the active site and the heme iron binding. The three most potent inhibitors (1, 17 and 18) appear to exploit interactions with C129 and S167 in the interior of the active site. All three inhibitors are approximately ten-fold more potent than 4-PI. The study represents the first example of enzyme inhibitor development with the recently reported crystal structure of IDO and offers important lessons in the search for more potent inhibitors.
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