In silico screening for Plasmodium falciparum enoyl-ACP reductase inhibitors.
In silico screening for Plasmodium falciparum enoyl-ACP reductase inhibitors.
复制标题
恶性疟原虫烯酰 ACP 还原酶抑制剂的计算机筛选。
DOI：
10.1007/s10822-014-9806-3
复制
发表时间：
2015
影响因子：
3.5
通讯作者：
McCammon,JAndrew
中科院分区：
文献类型：
--
作者：
Lindert,Steffen;Tallorin,Lorillee;Nguyen,QuynhG;Burkart,MichaelD;McCammon,JAndrew
由于最近出现了多药耐药的疟疾寄生虫，迫切需要针对恶性疟原虫的新疗法。由于脂肪酸对疟疾寄生虫的肝脏和血液阶段都是必不可少的，以脂肪酸生物合成为靶标是对抗P的一个有前途的策略。恶性疟原虫。我们提出了一项计算和实验相结合的研究，以确定脂肪酸生物合成途径中烯醇酰-酰基载体蛋白还原酶(PfENR)的新抑制剂。ChemBridge的一个小分子数据库被对接到三个不同的PfENR晶体结构中，这些结构提供了多种受体构象。两种不同的对接算法被用来生成共识分数，以便对可能的小分子命中进行排名。我们的研究导致了PfENR的五个低微摩尔的嘧啶二酮抑制剂的鉴定。
The need for novel therapeutics againstPlasmodium falciparumis urgent due to recent emergence of multi-drug resistant malaria parasites. Since fatty acids are essential for both the liver and blood stages of the malarial parasite, targeting fatty acid biosynthesis is a promising strategy for combattingP. falciparum. We present a combined computational and experimental study to identify novel inhibitors of enoyl-acyl carrier protein reductase (PfENR) in the fatty acid biosynthesis pathway. A small-molecule database from ChemBridge was docked into three distinctPfENR crystal structures that provide multiple receptor conformations. Two different docking algorithms were used to generate a consensus score in order to rank possible small molecule hits. Our studies led to the identification of five low-micromolar pyrimidine dione inhibitors ofPfENR.