Structure-Based Survey of the Binding Modes of BACE1 Inhibitors
文献类型：期刊论文
| 作者 | Hu, Hangchen; Chen, Zhaoqiang; Xu, Xiang; Xuo, Yechun |
| 刊名 | ACS CHEMICAL NEUROSCIENCE
 |
| 出版日期 | 2019-02-01 |
| 卷号 | 10期号:2页码:880-889 |
| 关键词 | BACE1 Alzheimer's disease inhibitor ligand binding mode subsite substructure |
| ISSN号 | 1948-7193 |
| DOI | 10.1021/acschemneuro.8b00420 |
| 通讯作者 | Xuo, Yechun(ycxu@simm.ac.cn) |
| 英文摘要 | BACE1 is a key aspartic protease that cleaves the amyloid precursor protein to generate of the amyloid peptide that is believed to be responsible for the Alzheimer's disease amyloid cascade. It is thus recognized as a promising therapeutic target for Alzheimer's disease treatment, and large efforts have been made in the discovery of novel BACE1 inhibitors. This Review presents a systematic mining of BACE1 inhibitors based on 354 crystal structures of the BACE1 catalytic domain in complex with ligands in the Protein Data Bank. A thorough exploration on the frequency as well as the patterns of residue-ligand interactions enables us to subdivide the ligand binding pocket into 10 subsites and then identify favorable substructures of ligands for each subsite. In addition, it is found that the assembly of subsites with an 8-like shape is responsible to bind all inhibitors and four major ligand binding modes are revealed. Thus, such a systematic survey deepens our understanding of the structural requirements for establishment of BACE1-ligand interactions that determine the affinity of a ligand to BACE1, which is pivotal for structure-based lead optimization and design of novel inhibitors. |
| WOS关键词 | STRUCTURE-BASED DESIGN ; AMYLOID PRECURSOR PROTEIN ; BETA-SECRETASE INHIBITORS ; X-RAY CRYSTALLOGRAPHY ; IN-VIVO REDUCTION ; ALZHEIMERS-DISEASE ; PEPTIDOMIMETIC INHIBITORS ; BIOLOGICAL EVALUATION ; SELECTIVE INHIBITORS ; CRYSTAL-STRUCTURE |
| 资助项目 | National Key R&D Program of China[2016YFA0502301] ; National Key R&D Program of China[2017YFB0202604] ; National Natural Science Foundation of China[81661148046] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology |
| 语种 | 英语 |
| WOS记录号 | WOS:000459642700012 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/290465]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Xuo, Yechun |
| 作者单位 | Chinese Acad Sci, CAS Key Lab Receptor Res, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Hu, Hangchen,Chen, Zhaoqiang,Xu, Xiang,et al. Structure-Based Survey of the Binding Modes of BACE1 Inhibitors[J]. ACS CHEMICAL NEUROSCIENCE,2019,10(2):880-889. |
| APA | Hu, Hangchen,Chen, Zhaoqiang,Xu, Xiang,&Xuo, Yechun.(2019).Structure-Based Survey of the Binding Modes of BACE1 Inhibitors.ACS CHEMICAL NEUROSCIENCE,10(2),880-889. |
| MLA | Hu, Hangchen,et al."Structure-Based Survey of the Binding Modes of BACE1 Inhibitors".ACS CHEMICAL NEUROSCIENCE 10.2(2019):880-889. |
入库方式： OAI收割
来源：上海药物研究所
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