Factors Influencing the Specificity of Inhibitor Binding to the Human and Malaria Parasite Dihydroorotate Dehydrogenases
Factors Influencing the Specificity of Inhibitor Binding to the Human and Malaria Parasite Dihydroorotate Dehydrogenases
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DOI：
10.1021/jm300157n
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发表时间：
2012-06-28
影响因子：
7.3
通讯作者：
Johnson, A. Peter
中科院分区：
文献类型：
--
作者：
Bedingfield, Paul T. P.;Cowen, Deborah;Johnson, A. Peter
从头嘧啶生物合成酶二氢乳清酸脱氢酶是治疗疟疾的新兴药物靶点。在这种情况下，恶性疟原虫 DHODH (PfDHODH) 的一个关键特性是它可以比其人类同源物 (HsDHODH) 被选择性抑制。然而，HsDHODH 也是治疗关节炎等自身免疫性疾病的经过验证的药物靶点。这里描述了一系列新型抑制剂，其中包括由于化学结构的微小改变而在两种酶之间切换特异性的化合物。构效关系 (SAR)、晶体学、对接和诱变研究用于检查两种酶内化合物的结合模式，并揭示抑制剂结合引起的结构变化。在该系列中，描述了具有治疗相关 HsDHODH 活性的化合物，并使用 X 射线晶体学表征了它们的结合模式，这揭示了抑制剂结合位点内的新构象转变。
The de novo pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase is an emerging drug target for the treatment of malaria. In this context a key property of Plasmodium falciparum DHODH (PfDHODH) is that it can be selectively inhibited over its human homologue (HsDHODH). However, HsDHODH is also a validated drug target for autoimmune diseases such as arthritis. Here a series of novel inhibitors is described that includes compounds that switch specificity between the two enzymes as a result of small alterations in chemical structure. Structure-activity relationship (SAR), crystallography, docking, and mutagenesis studies are used to examine the binding modes of the compounds within the two enzymes and to reveal structural changes induced by inhibitor binding. Within this series, compounds with therapeutically relevant HsDHODH activity are described and their binding modes characterized using X-ray crystallography, which reveals a novel conformational shift within the inhibitor binding site.