Microsecond molecular dynamics simulation of A beta(42) and identification of a novel dual inhibitor of A beta(42) aggregation and BACE1 activity
文献类型：期刊论文
| 作者 | Wang, Yuan-yuan; Li, Li; Chen, Tian-tian; Chen, Wu-yan; Xu, Ye-chun
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| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2013-09 |
| 卷号 | 34期号:9页码:1243-1250 |
| 关键词 | amyloid beta-peptide (A beta) beta-secretase Alzheimer's disease (AD) dual inhibitor structure-based virtual screening molecular dynamics (MD) simulation |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2013.55 |
| 文献子类 | Article |
| 英文摘要 | Aim: To study the conformational changes of A beta(42) and discover novel inhibitors of both A beta(42) aggregation and beta-secretase (BACE1). Methods: A molecular dynamics (MD) simulation at a microsecond level was performed to explore stable conformations of A beta(42) monomer in aqueous solution. Subsequently, structure-based virtual screening was used to search for inhibitors of both A beta(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 a-helical conformation of A beta(42), which was unstable in aqueous solution, turned into a beta-sheet mixed with a coil structure through a transient and fully random coil. The conformation of A beta(42) mainly comprising beta-sheets and coils structure was used for further virtual screening. Five compounds were identified as inhibitors for A beta(42) aggregation, and one of them, AE-848, was discovered to be a dual inhibitor of both A beta(42) aggregation and BACE1, with IC50 values of 36.95 mu mol/L and 22.70 mu mol/L, respectively. Conclusion: A helical to beta-sheet conformational change in A beta(42) occurred in a 1.8 microsecond MD simulation. The resulting beta-sheet structure of the peptide is an appropriate conformation for the virtual screening of inhibitors against A beta(42) aggregation. Five compounds were identified as inhibitors of A beta(42) aggregation by in vitro activity assays. It was particularly interesting to discover a dual inhibitor that targets both A beta(42) aggregation and BACE1, the two crucial players in the pathogenesis of Alzheimer's disease. |
| WOS关键词 | AMYLOID-BETA-PROTEIN ; ALZHEIMERS-DISEASE ; CONFORMATIONAL TRANSITION ; CRYSTAL-STRUCTURE ; PEPTIDE ; ENZYME ; ENVIRONMENT ; DISCOVERY ; PRECURSOR ; OLIGOMER |
| 资助项目 | "100 Talents Project" of CAS[00000000] ; State Key Program of Basic Research of China[2009CB918501] ; National Natural Science Foundation of China[91013010] ; National Natural Science Foundation of China[21172233] ; National Supercomputing Center in Tianjin (Tianhe-1)[00000000] ; Shanghai Supercomputer Center[00000000] ; Computer Network Information Center of the Chinese Academy of Sciences[00000000] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:4921452 |
| WOS记录号 | WOS:000324170400015 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277478]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Xu, Ye-chun |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Yuan-yuan,Li, Li,Chen, Tian-tian,et al. Microsecond molecular dynamics simulation of A beta(42) and identification of a novel dual inhibitor of A beta(42) aggregation and BACE1 activity[J]. ACTA PHARMACOLOGICA SINICA,2013,34(9):1243-1250. |
| APA | Wang, Yuan-yuan,Li, Li,Chen, Tian-tian,Chen, Wu-yan,&Xu, Ye-chun.(2013).Microsecond molecular dynamics simulation of A beta(42) and identification of a novel dual inhibitor of A beta(42) aggregation and BACE1 activity.ACTA PHARMACOLOGICA SINICA,34(9),1243-1250. |
| MLA | Wang, Yuan-yuan,et al."Microsecond molecular dynamics simulation of A beta(42) and identification of a novel dual inhibitor of A beta(42) aggregation and BACE1 activity".ACTA PHARMACOLOGICA SINICA 34.9(2013):1243-1250. |
入库方式： OAI收割
来源：上海药物研究所
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