Conformational flexibility of beta-secretase: molecular dynamics simulation and essential dynamics analysis
文献类型：期刊论文
| 作者 | Xiong, B ; Huang, XQ; Shen, LL; Shen, JH; Luo, XM; Shen, X; Jiang, HL; Chen, KX
|
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2004-06 |
| 卷号 | 25期号:6页码:705-713 |
| 关键词 | molecular dynamics secretase essential dynamics computer simulation Alzheimer disease |
| ISSN号 | 1671-4083 |
| 文献子类 | Article |
| 英文摘要 | AIM: Based on the structural analysis to reveal the mechanism of ligand binding to beta-secretase and the specificity of each binding sub-site. METHODS: Molecular dynamics was used to simulate on the ligand free beta-secretase and ligand bound beta-secretase. The trajectories were analyzed using the essential dynamics, and the significant conformational change was illustrated employing the DynDom program. RESULTS: The essential dynamics and DynDom analyses clearly showed that the beta-secretase experienced a large conformational change upon the substrate or inhibitor binding. The flap structure adopted a swing motion, gradually covering the active site to facilitate the ligand binding process. Residues Ser86 and Ile87 served as the hinge point. Inhibitor-enzyme interaction analysis revealed that residues at P2, P1, and P1' positions of the inhibitor were very important for the binding, and residues at P2' and P3' positions may be modified to improve the binding specificity. S3 subsite of the enzyme still had space to modify the inhibitors in increasing the binding affinity. CONCLUSION: The information presented here is valuable and could be used to identify small molecular inhibitors of beta-secretase. |
| WOS关键词 | AMYLOID PRECURSOR PROTEIN ; ALZHEIMERS-DISEASE ; DRUG TARGET ; HUMAN BRAIN ; INHIBITOR ; SYSTEM ; DOMAIN ; BACE ; SITE |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000221833900001 |
| 出版者 | SHANGHAI INST MATERIA MEDICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/274064]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物化学研究室 |
| 通讯作者 | Shen, JH |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res,Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xiong, B,Huang, XQ,Shen, LL,et al. Conformational flexibility of beta-secretase: molecular dynamics simulation and essential dynamics analysis[J]. ACTA PHARMACOLOGICA SINICA,2004,25(6):705-713. |
| APA | Xiong, B.,Huang, XQ.,Shen, LL.,Shen, JH.,Luo, XM.,...&Chen, KX.(2004).Conformational flexibility of beta-secretase: molecular dynamics simulation and essential dynamics analysis.ACTA PHARMACOLOGICA SINICA,25(6),705-713. |
| MLA | Xiong, B,et al."Conformational flexibility of beta-secretase: molecular dynamics simulation and essential dynamics analysis".ACTA PHARMACOLOGICA SINICA 25.6(2004):705-713. |
入库方式： OAI收割
来源：上海药物研究所
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