Binding of nonsteroidal anti-inflammatory drugs to Abeta fibril.
Binding of nonsteroidal anti-inflammatory drugs to Abeta fibril.
复制标题
非甾体抗炎药与 Abeta 原纤维的结合。
DOI：
10.1002/prot.22804
复制
发表时间：
2010
期刊：
影响因子：
2.9
通讯作者：
Klimov,DmitriK
中科院分区：
文献类型：
--
作者：
Takeda,Takako;Chang,WenlingE;Raman,EPrabhu;Klimov,DmitriK
非甾体抗炎药被认为是治疗阿尔茨海默病的潜在药物。利用复制交换分子动力学和原子隐式溶剂模型，我们研究了萘普生和布洛芬与由固态NMR测量得到的Aβ纤维的结合机制。发现萘普生的结合温度比布洛芬高几乎40 K，这意味着萘普生的结合亲和力更高。增强萘普生结合的关键因素是与原纤维表面结合的配体之间的强相互作用。萘环中的萘环似乎对配体-配体相互作用提供了主要贡献。相反，配体-原纤维相互作用不能解释萘普生和布洛芬结合亲和力的差异。具有凹槽的凹原纤维边缘被鉴定为两种配体的主要结合位置。我们表明，限制的配位体的凹槽促进配位体-配位体的相互作用，降低了能量的配位体绑定到凹边缘相比，那些绑定到凸边缘。我们的模拟似乎提供了不同的结合亲和力的萘普生和布洛芬实验观察微观的理由。Proteins 2010.© 2010 Wiley利斯公司
Nonsteroidal anti‐inflammatory drugs are considered as potential therapeutic agents against Alzheimer's disease. Using replica exchange molecular dynamics and atomistic implicit solvent model, we studied the mechanisms of binding of naproxen and ibuprofen to the Aβ fibril derived from solid‐state NMR measurements. The binding temperature of naproxen is found to be almost 40 K higher than of ibuprofen implicating higher binding affinity of naproxen. The key factor, which enhances naproxen binding, is strong interactions between ligands bound to the surface of the fibril. The naphthalene ring in naproxen appears to provide a dominant contribution to ligand‐ligand interactions. In contrast, ligand‐fibril interactions cannot explain differences in the binding affinities of naproxen and ibuprofen. The concave fibril edge with the groove is identified as the primary binding location for both ligands. We show that confinement of the ligands to the groove facilitates ligand‐ligand interactions that lowers the energy of the ligands bound to the concave edge compared with those bound to the convex edge. Our simulations appear to provide microscopic rationale for the differing binding affinities of naproxen and ibuprofen observed experimentally. Proteins 2010. © 2010 Wiley‐Liss, Inc.