神经氨酸酶与三羟基甲氧基黄酮衍生物相互作用的分子模拟

Molecular Simulation of Interaction Mechanisms of Neuraminidase and Trihydroxy-methoxyflavone Derivatives

以5,7,4'-三羟基-8-甲氧基黄酮(MF)为先导物,以现有的神经氨酸酶(NA)抑制剂类药物的结构特征为参考,设计了一系列的三羟基甲氧基黄酮衍生物,并运用分子对接与分子动力学相结合的方法进行了筛选及作用机制分析.分子对接结果表明,功能团(羧基及胍基/氮-乙酰氨基)的引入并未影响衍生物在酶活性腔中的结合位置,衍生物的结构与相互作用能之间存在一定的联系.将羧基和胍基作为替代基团引入到MF的C7及C5位上所得的新化合物(9)在所合成的衍生物中具有最好的结合能力(-1172.52 kJ/mol),远远优于现有先导药物4-(氮-乙酰氨基)-5-胍基-3-(3-戊氧基)安息香酸(BA)和MF与NA的结合能力(-672.12和-347.44 kJ/mol).进一步的作用机制分析发现,在神经氨酸酶活性腔中,化合物9的羧基和胍基的空间取向与现有药物中这两个基团的空间取向一致,且化合物9与先导药物MF一样,能与活性腔内保守残基Asp151和Glu227发生较强的相互作用.因此可认为化合物9是一种具有应用潜质的新型神经氨酸酶抑制剂.本研究结果为实验研究和设计抗流感药物提供了可行性思路.

A series of trihydroxy-methoxyflavone （MF） analogues was designed starting from MF, contracts that reference structural characters of the existing neuraminidase inhibitors. The docking and molecular dyna- mics simulations were carried out, aiming to discover the novel antiviral agents and contribute to the under- standing on the interacting mechanisms. It is found that the binding locations of derivatives at the neuramini- dase active site will not be influenced much with the addition of functional groups（ earboxyl and guanidino/N- acetylamino）, and there are some connections between the structures of derivatives and their interaction ener- gies. Compound 9, with the replacements of carboxyl and guanidino groups at C7 and C5 of MF, demonstrates the highest interaction energy among the covered derivatives, equals -1172. 52 kJ/mol, and is larger than the values of available lead drugs BA and MF（ -672. 12 and -347.44 kJ/mol）. The space orientations of carbox- yl and guanidino groups within the compound 9 at the neuraminidase active site are in good agreement with the current drugs. In addition, compound 9 has strong interactions with the conserved active-site residues Aspl51 and Glu227, which is similar to the situation of MF. Therefore, compound 9 is a novel neuraminidase inhibitor with potential applications. We hope that these results will arouse the interest of experimental aspects to design novel anti-influenza drugs.