神经氨酸酶与3-(3-戊氧基)安息香酸作用机制的理论研究

A Computational Investigation on the Interaction Mechanisms of Neuraminidases and 3-(3-Pentyloxy)benzoic Acid

运用柔性分子对接和分子动力学方法,深入研究了4-(氮乙酰氨基)-5-胍基-3-(3-戊氧基)安息香酸(BA)与各类型神经氨酸酶(N1,N2,N9亚型和B型)间的作用机制.结果显示,BA与各类型神经氨酸酶结合模式存在差异,但作用机制比较相似:与它们的活性腔均匹配良好,并形成稳定的复合体系,最大结合能分别等于-1233.62,-1385.72,-663.11,-1058.87kJ·mol-1.这表明BA对各类型神经氨酸酶均有良好的抑制效果.进一步分析发现,BA与各类型神经氨酸酶活性腔内保守关键氨基酸残基发生较强的静电和氢键作用,而与易突变氨基酸残基作用较弱,表明了活性腔内易突变氨基酸残基发生突变也不会对抑制效果造成明显影响.因此,BA是一种极具应用前景的新型抗流感病毒药物.结合以前的研究结果,我们提出了以BA为底物的抗流感病毒药物的修饰方向.

With the aid of flexible docking and molecular dynamics methods,an in-depth investigation is carried out on the binding mechanisms of 4-（N-acetylamino）-5-guanidino-3-（3-pentyloxy）benzoic acid（BA） with various types of neuraminidases（N1,N2 and N9 subtypes and B type）.It indicates that BA is docked to the various types of neuraminidases with similar mechanisms,albeit some differences exist in the binding poses.BA matches their active sites well and forms stable complexes.The largest binding affinities with N1,N2 and N9 subtypes and B type are calculated to be-1233.62,-1385.72,-663.11 and-1058.87 kJ·mol^-1,respectively.It suggests that BA has excellent inhibiting effects to all the studied neuraminidases.The further analyses reveal that strong electrostatic and H-bonding interactions exist between BA and the conserved key active-site residues instead of the facile-mutated ones,indicating that the inhibiting effects will not be influenced obviously by mutations.Accordingly,BA is a potential anti-influenza virus drug worthy of more attention.Combined with the previous studies,we point out how to modify the BA molecule in order to enhance the inhibiting effects to the neuraminidases.