Computer-Aided Identification of Trypanosoma brucei Uridine Diphosphate Galactose 4′-Epimerase Inhibitors: Toward the Development of Novel Therapies for African Sleeping Sickness
Computer-Aided Identification of Trypanosoma brucei Uridine Diphosphate Galactose 4′-Epimerase Inhibitors: Toward the Development of Novel Therapies for African Sleeping Sickness
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DOI：
10.1021/jm100456a
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发表时间：
2010-07-08
影响因子：
7.3
通讯作者：
McCammon, J. Andrew
中科院分区：
文献类型：
--
作者：
Durrant, Jacob D.;Urbaniak, Michael D.;McCammon, J. Andrew
布氏锥虫是非洲人类锥虫病的病原体，影响着撒哈拉以南非洲数万人。由于当前的治疗方法因毒副作用、耐药性和疗效有限而不尽人意，迫切需要新的治疗方法。UDP - 半乳糖4'-差向异构酶（TbGalE）是半乳糖代谢的勒洛尔途径中的一种酶，是一个很有前景的布氏锥虫药物靶点。我们在此使用松弛复合物方案，这是一种考虑蛋白质完全柔性的先进计算机对接方法，来识别TbGalE的抑制剂。在100μM浓度下，最初获得了62%的命中率，最终确定了14种低微摩尔浓度的抑制剂。这些抑制剂中有13种属于一个具有保守结合基序的独特系列，这可能在未来的药物设计和优化中有用。
Trypanosoma brucei, the causative agent of human African trypanosomiasis, affects tens of thousands of sub-Saharan Africans. As current therapeutics are inadequate due to toxic side effects, drug resistance, and limited effectiveness, novel therapies are urgently needed. UDP-galactose 4'-epimerase (TbGalE), an enzyme of the Leloir pathway of galactose metabolism, is one promising T. brucei drug target. We here use the relaxed complex scheme, an advanced computer-docking methodology that accounts for full protein flexibility, to identify inhibitors of TbGalE. An initial hit rate of 62% was obtained at 100 mu M, ultimately leading to the identification of 14 low-micromolar inhibitors. Thirteen of these inhibitors belong to a distinct series with a conserved binding motif that may prove useful in future drug design and optimization.