Fogel Gary B, Cheung Mars, Pittman Eric, Hecht David
Natural Selection, Inc., 9330 Scranton Road, Suite 150, San Diego, CA 92121, USA.
J Comput Aided Mol Des. 2008 Jan;22(1):29-38. doi: 10.1007/s10822-007-9152-9. Epub 2007 Dec 11.
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.
对已知的恶性疟原虫四重突变二氢叶酸还原酶（DHFR）抑制剂进行了建模研究。使用GOLD将32种乙胺嘧啶衍生物对接至从x射线晶体结构1J3K.pdb获得的DHFR活性位点。评估了几种评分函数，确定Molegro蛋白质-配体相互作用评分与实验pK（i）具有最佳相关性之一。结合蛋白质-配体相互作用评分，评估和分析预测的结合模式和关键蛋白质-配体相互作用，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。该方法将用于未来研究中聚焦筛选文库化合物的选择。
