鉴定和开发新型刚地弓形虫烯醇还原酶抑制剂。
Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase.
机构信息
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA.
出版信息
J Med Chem. 2010 Sep 9;53(17):6287-300. doi: 10.1021/jm9017724.
Toxoplasmosis causes significant morbidity and mortality, and yet available medicines are limited by toxicities and hypersensitivity. Because improved medicines are needed urgently, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a type II fatty acid synthase enzyme essential in parasites but not present in animals. Fifty-three compounds, including three classes that inhibit ENRs, were tested. Six compounds have antiparasite MIC(90)s < or = 6 microM without toxicity to host cells, three compounds have IC(90)s < 45 nM against recombinant TgENR, and two protect mice. To further understand the mode of inhibition, the cocrystal structure of one of the most promising candidate compounds in complex with TgENR has been determined to 2.7 A. The crystal structure reveals that the aliphatic side chain of compound 19 occupies, as predicted, space made available by replacement of a bulky hydrophobic residue in homologous bacterial ENRs by Ala in TgENR. This provides a paradigm, conceptual foundation, reagents, and lead compounds for future rational development and discovery of improved inhibitors of T. gondii.
弓形虫病可导致严重的发病率和死亡率，但现有的药物受到毒性和过敏反应的限制。由于急需改进的药物，因此采用合理的方法来鉴定新型的有效针对弓形虫烯醇还原酶（TgENR）的先导化合物，该酶是寄生虫中必需的 II 型脂肪酸合酶酶，但在动物中不存在。测试了 53 种化合物，包括抑制 ENR 的三种类型。六种化合物具有抗寄生虫 MIC（90）<或= 6μM 而对宿主细胞无毒性，三种化合物对重组 TgENR 的 IC（90）<45 nM，两种化合物可保护小鼠。为了进一步了解抑制机制，已确定与 TgENR 形成复合物的一种最有前途的候选化合物的晶体结构至 2.7A。晶体结构表明，化合物 19 的脂侧链占据了预测的空间，这是由同源细菌 ENR 中一个大的疏水性残基被 TgENR 中的 Ala 取代所产生的。这为未来合理开发和发现更好的弓形虫抑制剂提供了范例、概念基础、试剂和先导化合物。
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