Modeling the inhibition of quadruple mutant Plasmodium falciparum dihydrofolate reductase by pyrimethamine derivatives
Modeling the inhibition of quadruple mutant Plasmodium falciparum dihydrofolate reductase by pyrimethamine derivatives
复制标题
DOI：
10.1007/s10822-007-9152-9
复制
发表时间：
2008-01-01
影响因子：
3.5
通讯作者：
Hecht, David
中科院分区：
文献类型：
--
作者：
Fogel, Gary B.;Cheung, Mars;Hecht, David
对已知的四重突变恶性疟原虫二氢叶酸还原酶（DHFR）抑制剂进行了建模研究。用GOLD将32个乙胺嘧啶衍生物对接到从x射线晶体结构1J3K.pdb得到的DHFR活性位点上。对多个评分函数进行了评估，确定Molegro蛋白-配体相互作用评分（Molegro Protein-Ligand Interaction Score）与实验pK的相关性最好。结合蛋白-配体相互作用评分，对预测的结合模式和关键的蛋白-配体相互作用进行了评估和分析，以制定选择对恶性疟原虫耐药菌株具有更大活性机会的化合物的标准。该方法将在未来的研究中用于重点筛选文库的化合物选择。
Modeling studies were performed on known inhibitors of the quadruple mutant Plasmodium falciparum dihydrofolate reductase (DHFR). GOLD was used to dock 32 pyrimethamine derivatives into the active site of DHFR obtained from the x-ray crystal structure 1J3K.pdb. Several scoring functions were evaluated and the Molegro Protein-Ligand Interaction Score was determined to have one of the best correlation to experimental pK (i) . In conjunction with Protein-Ligand Interaction scores, predicted binding modes and key protein-ligand interactions were evaluated and analyzed in order to develop criteria for selecting compounds having a greater chance of activity versus resistant strains of Plasmodium falciparum. This methodology will be used in future studies for selection of compounds for focused screening libraries.