摘要
本研究以H5N1亚型流感病毒神经氨酸酶(NA)活性位点旁的"150-空穴"为靶标,采用半柔性分子对接计算机模拟技术,设计并合成了一种绿原酸的结构类似物——4-(咖啡酰基)氨基丁酸,计算机模拟结果显示该化合物能够插入到N1"150-空穴"中并和Arg156侧链以氢键的方式结合,与N1的最佳结合自由能为-7.70 kcal.mol-1,与奥司他韦相当。同时,利用以H5N1假病毒体系为基础建立的NA抑制剂筛选模型,测定了奥司他韦、绿原酸和4-(咖啡酰基)氨基丁酸对NA的抑制作用,发现与绿原酸相比,4-(咖啡酰基)氨基丁酸显著增强了对N1型神经氨酸酶的抑制作用,但与奥司他韦仍有一定的差距。本实验初步探索了"150-空穴"作为新型神经氨酸酶抑制剂靶标的可能性,为开发新型神经氨酸酶抑制剂提供了新的思路。
In this study,the ＂150-cavity＂,next to the H5N1 influenza virus neuraminidase activity site,has been used as the target to design and synthesize a structural analogue of chlorogenic acid,N-caffeoyl-GABA,using the flexible docking simulation.The docking study showed that the N-caffeoyl-GABA could be inserted into the ＂150-cavity＂ and combined with the Arg156 side chain by hydrogen bond.The best binding free energy of H5N1 NA-N-caffeoyl-GABA complex was-7.70 kcal·mol-1,equivalent that of the NA-oseltamivir.At the same time,using the H5N1 pseudotyping virus-based NA inhibitors screening model,we determined the inhibitory effect of oseltamivir,chlorogenic acid and N-caffeoyl-GABA on the NA.Compared with chlorogenic acid,N-caffeoyl-GABA significantly enhanced the inhibitory effect on NA,but less than oseltamivir.This study showed that the ＂150-cavity＂ could possibly be used as a new neuraminidase inhibitors target,and provided a path for the development of new neuraminidase inhibitors.
出处
《药学学报》
CAS
CSCD
北大核心
2011年第11期1344-1348,共5页
Acta Pharmaceutica Sinica
基金
湖北省教育厅自然科学基金资助项目(Q20111201)
