一种新型流感病毒神经氨酸酶抑制剂的设计、合成及活性研究

杨 帆 金 蕾 黄年玉 程峰 罗华军 陈剑锋

一种新型流感病毒神经氨酸酶抑制剂的设计、合成及活性研究

杨帆金蕾黄年玉程峰罗华军陈剑锋

Design, synthesis and activity of a new type of influenza virus N1 neuraminidase inhibitors

YANG Fan

摘要

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。

Abstract:
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.

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