摘要
为实现除草剂先导化合物的作用靶标快速、精准预测以及活性分析,本试验建立了一种快速高效的基于化合物结构的反向寻找除草剂靶标的计算机模拟方法。通过分析拟南芥(Arabidopsis thaliana)的KEGG(京都基因与基因组百科全书)氨基酸代谢通路图(ath00460),筛选出调节氨基酸生物合成中的关键蛋白;利用YASARA软件对蛋白质三维结构模型进行同源模建以及Autodock vina 4.0软件模拟化合物小分子与靶蛋白的相互作用的方法,对筛选得到调节生成氨基酸中间产物或最终产物的专一性蛋白进行靶标库的建立,随后利用已知作用靶标的化合物分子进行了可行性与可靠性的验证,建立了一种基于化合物结构的反向寻找靶标的计算机模拟方法。通过筛选分析得到了166个调节生成关键中间产物或最终产物的专一性蛋白(涵盖已报道的18种与氨基酸生物合成途径有关的除草剂靶标酶),其中18个蛋白从PDB数据库中下载晶体结构,148个蛋白利用YASARA同源模建;利用烟嘧磺隆、甲磺隆、苯磺隆、灭草喹、多菌灵、毒死蜱六个已知作用靶标的化合物分子进行了可行性与可靠性的验证。本试验得到一种快速高效的基于化合物结构的反向寻找除草剂靶标的计算机模拟方法,该方法能快速、准确地预测小分子化合物的靶点与未知化合物的生物活性,为新农药创制的提供参考依据。
In order to get fast accurate prediction and activity analysis of herbicide lead compounds,the experiment established a fast and efficient computer simulation method based on compound structure for reverse search of herbicide targets.By analyzing the KEGG amino acid metabolic pathway map（Kyoto Encyclopedia of Genes and Genomes,ath00460）of Arabidopsis thaliana,the key proteins in the regulation of amino acid biosynthesis were screened.Using YASARA software to perform homology modeling on the three-dimensional structure model of the protein and Autodock vina4.0 software to simulate the interaction between the small molecule of the compound and the target protein.The specific protein that regulates the production of an amino acid intermediate or final product was used to establish a target library.Subsequently,the feasibility and reliability of the compound molecules were performed with known target molecules and the computer simulation method based on compound structure for reverse finding target was established.Through screening analysis,166 specific proteins（including the reported herbicide target enzymes related to amino acid biosynthesis pathways）that regulate the production of key intermediates or final products were obtained,of which 18 proteins were downloaded from the PDB database,148 proteins were constructed using YASARA homology,The feasibility and reliability of the system were verified by the compound molecules of nicosulfuron,metsulfuron-methyl,tribenuron-methyl,chlorfenapyr,carbendazim and chlorpyrifos.The experiment yields a fast and efficient computer simulation method for reverse-seeking herbicide targets based on compound structures.The method can quickly and accurately predict the target of small molecule compounds and biological activity of unknown compounds,which provides references for the discovery of new pesticides.
作者
董存涛
高卫
霍静倩
张金林
曾思瑜
DONG Cun-tao;GAO Wei;HUO Jing-qian;ZHANG Jin-lin;ZENG Si-yu(College of Plant Protection,Agricultural University of Hebei,Baoding 071001,China;Kairui Environmental Protection Co.ltd.,Cangzhou 061000,China)
出处
《河北农业大学学报》
CAS
CSCD
北大核心
2018年第4期42-49,共8页
Journal of Hebei Agricultural University
基金
国家自然科学基金资助项目(31471786)
关键词
除草剂
靶标库
反向分子对接
氨基酸代谢
herbicide
target library
reverse molecular docking
amino acidmetabolism
