On the lower susceptibility of oseltamivir to influenza neuraminidase subtype N1 than those in N2 and N9
On the lower susceptibility of oseltamivir to influenza neuraminidase subtype N1 than those in N2 and N9
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DOI：
10.1529/biophysj.106.092528
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发表时间：
2007-02-01
影响因子：
3.4
通讯作者：
Hannongbua, Supot
中科院分区：
文献类型：
--
作者：
Aruksakunwong, Ornjira;Malaisree, Maturos;Hannongbua, Supot
为了在分子水平上理解为什么奥司他韦（OTV）不能像抑制N2和N9亚型那样有效地抑制N1亚型人流感神经氨酸酶，对三种复合物OTV-N1、OTV-N2和OTV-N9进行了分子动力学模拟。三维OTV-N2和OTV-N9初始结构由X射线结构表示，而OTV-N1的初始结构（其X射线结构尚未解析）是使用从泰国人分离的H5 N1的比对序列以N2-底物的X射线结构作为模板建立的。与OTV-N2和OTV-N9复合物相比，在OTV-N1复合物中观察到OTV构象的显著变化，其中其两个庞大的侧链，N-乙酰基（-NHAc）和1-乙基代理基团（-OCHEt 2）被旋转以调节大小以适应N1催化位点。这种变化直接导致OTV的环境发生了重排，即：（1）OTV与W-178和E-227的距离变短，而与R-224、E-276和E-292的距离变长，（2）OTV与R-224和E- 276的氢键在距离、数量和占有率上保持不变; iii）计算的配体/酶结合自由能为-7.20、-13.44和-13.29 kcal/mol，与它们的抑制活性一致，就OTV-N1、OTV-N2和OTV-N9复合物的实验IC 50而言，分别为36.1-53.2 nM、1.9-2.7 nM和9.5-17.7 nM;和iv）OTV和邻近残基之间的氢键断裂和产生相应地与催化位点中发生的配体溶剂化/去溶剂化一致。
Aiming to understand, at the molecular level, why oseltamivir (OTV) cannot be used for inhibition of human influenza neuraminidase subtype N1 as effectively as for subtypes N2 and N9, molecular dynamics simulations were carried out for the three complexes, OTV-N1, OTV-N2, and OTV-N9. The three-dimensional OTV-N2 and OTV-N9 initial structures were represented by the x-ray structures, whereas that of OTV-N1, whose x-ray structure is not yet solved, was built up using the aligned sequence of H5N1 isolated from humans in Thailand with the x-ray structure of the N2-substrate as the template. In comparison to the OTV-N2 and OTV-N9 complexes, dramatic changes were observed in the OTV conformation in the OTV-N1 complex in which two of its bulky side chains, N-acethyl (-NHAc) and 1-ethylproxy group (-OCHEt2), were rotated to adjust the size to fit into the N1 catalytic site. This change leads directly to the rearrangements of the OTV's environment, which are i), distances to its neighbors, W-178 and E-227, are shorter whereas those to residues R-224, E-276, and E-292 are longer; ii), hydrogen bonds to the two nearest neighbors, R-224 and E- 276, are still conserved in distance and number as well as percentage occupation; iii), the calculated ligand/enzyme binding free energies of -7.20, -13.44, and -13.29 kcal/mol agree with their inhibitory activities in terms of the experimental IC50 of 36.1-53.2 nM, 1.9-2.7 nM, and 9.5-17.7 nM for the OTV-N1, OTV-N2, and OTV-N9 complexes, respectively; and iv), hydrogen-bond breaking and creation between the OTV and neighborhood residues are accordingly in agreement with the ligand solvation/desolvation taking place in the catalytic site.