Department of Bioinformatics and Computational Biology, George Mason University, Manassas, Virginia 20110, USA.
J Phys Chem B. 2010 Nov 25;114(46):15394-402. doi: 10.1021/jp107955v. Epub 2010 Oct 27.
Using implicit solvent model and replica exchange molecular dynamics, we examine the propensity of a nonsteroidal anti-inflammatory drug, naproxen, to interfere with Aβ fibril growth. We also compare the antiaggregation propensity of naproxen with that of ibuprofen. Naproxen's antiaggregation effect is influenced by two factors. Similar to ibuprofen, naproxen destabilizes binding of incoming Aβ peptides to the fibril due to direct competition between the ligands and the peptides for the same binding location on the fibril surface (the edge). However, in contrast to ibuprofen, naproxen binding also alters the conformational ensemble of Aβ monomers by promoting β-structure. The second factor weakens naproxen's antiaggregation effect. These findings appear to explain the experimental observations, in which naproxen binds to the Aβ fibril with higher affinity than ibuprofen, yet produces weaker antiaggregation action.
利用隐溶剂模型和复制交换分子动力学，我们研究了一种非甾体抗炎药萘普生抑制 Aβ 纤维生长的倾向。我们还比较了萘普生与布洛芬的抗聚集倾向。萘普生的抗聚集作用受两个因素影响。与布洛芬相似，由于配体和肽之间在纤维表面（边缘）的相同结合位置上的直接竞争，萘普生使进入的 Aβ 肽与纤维的结合不稳定。然而，与布洛芬不同的是，萘普生的结合还通过促进β结构改变 Aβ 单体的构象集合。第二个因素削弱了萘普生的抗聚集作用。这些发现似乎解释了实验观察结果，即萘普生与 Aβ 纤维的结合亲和力高于布洛芬，但产生的抗聚集作用较弱。
