microsecondmoleculardynamicssimulationofa42andidentificationofanoveldualinhibitorofa42aggregationandbace1activity
文献类型：期刊论文
| 作者 | Wang Yuanyuan; Li Li; Chen Tiantian; Chen Wuyan; Xu Yechun
|
| 刊名 | actapharmacologicasinica
 |
| 出版日期 | 2013 |
| 卷号 | 34期号:9页码:1243 |
| 关键词 | amyloid β-peptide (Aβ) β-secretase Alzheimer’s disease (AD) dual inhibitor structure-based virtual screening molecular dynamics (MD) simulation |
| ISSN号 | 1671-4083 |
| 英文摘要 | Aim: To study the conformational changes of Aβ_(42) and discover novel inhibitors of both Aβ_(42) aggregation and β-secretase (BACE1). Methods: A molecular dynamics (MD) simulation at a microsecond level was performed to explore stable conformations of Aβ_(42) monomer in aqueous solution. Subsequently, structure-based virtual screening was used to search for inhibitors of both Aβ_(42) aggregation and BACE1. Protein purification and in vitro activity assays were performed to validate the inhibition of the compounds identified via virtual screening.Results: The initial α-helical conformation of Aβ_(42), which was unstable in aqueous solution, turned into a β-sheet mixed with a coil structure through a transient and fully random coil. The conformation of Aβ_(42) mainly comprising β-sheets and coils structure was used for further virtual screening. Five compounds were identified as inhibitors for Aβ_(42) aggregation, and one of them, AE-848, was discovered to be a dual inhibitor of both Aβ_(42) aggregation and BACE1, with IC_(50) values of 36.95 μmol/L and 22.70 μmol/L, respectively.Conclusion: A helical to β-sheet conformational change in Aβ_(42) occurred in a 1.8 microsecond MD simulation. The resulting β-sheet structure of the peptide is an appropriate conformation for the virtual screening of inhibitors against Aβ_(42) aggregation. Five compounds were identified as inhibitors of Aβ_(42) aggregation by in vitro activity assays. It was particularly interesting to discover a dual inhibitor that targets both Aβ_(42) aggregation and BACE1, the two crucial players in the pathogenesis of Alzheimer’s disease. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/286335]  |
| 专题 | 中国科学院上海药物研究所 |
| 作者单位 | 中国科学院上海药物研究所 |
| 推荐引用方式 GB/T 7714 | Wang Yuanyuan,Li Li,Chen Tiantian,et al. microsecondmoleculardynamicssimulationofa42andidentificationofanoveldualinhibitorofa42aggregationandbace1activity[J]. actapharmacologicasinica,2013,34(9):1243. |
| APA | Wang Yuanyuan,Li Li,Chen Tiantian,Chen Wuyan,&Xu Yechun.(2013).microsecondmoleculardynamicssimulationofa42andidentificationofanoveldualinhibitorofa42aggregationandbace1activity.actapharmacologicasinica,34(9),1243. |
| MLA | Wang Yuanyuan,et al."microsecondmoleculardynamicssimulationofa42andidentificationofanoveldualinhibitorofa42aggregationandbace1activity".actapharmacologicasinica 34.9(2013):1243. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。