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Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent beta-secretase (BACE1) Inhibitors

文献类型：期刊论文

作者Zou, Yiquan2; Li, Li1; Chen, Wuyan1; Chen, Tiantian1; Ma, Lanping2; Wang, Xin2; Xiong, Bing2; Xu, Yechun1; Shen, Jingkang2
刊名MOLECULES
出版日期2013-05
卷号18期号:5页码:5706-5722
关键词virtual screening docking structure-based lead design crystal structure indole acylguanidine
ISSN号1420-3049
DOI10.3390/molecules18055706
文献子类Article
英文摘要Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE1) is a key step in generating the N-terminal of beta-amyloid (A beta), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer's disease. Inhibitors of BACE1 can reduce the levels of A beta and thus have a therapeutic potential for treating the disease. We report here the identification of a series of small molecules bearing an indole acylguanidine core structure as potent BACE1 inhibitors. The initial weak fragment was discovered by virtual screening, and followed with a hit-to-lead optimization. With the aid of co-crystal structures of two discovered inhibitors (compounds 19 and 25) with BACE1, we explored the SAR around the indole and aryl groups, and obtained several BACE1 inhibitors about 1,000-fold more potent than the initial fragment hit. Accompanying the lead optimization, a previously under-explored sub-site opposite the flap loop was redefined as a potential binding site for later BACE1 inhibitor design.
WOS关键词STRUCTURE-BASED DESIGN ; X-RAY CRYSTALLOGRAPHY ; ALZHEIMERS-DISEASE ; PEPTIDOMIMETIC INHIBITORS ; THERAPEUTICS ; OPTIMIZATION ; ANTAGONISTS ; GENERATION ; PROGRESS ; PROTEIN
资助项目Excellent Young Scientist of Chinese Academy of Sciences[KSCX2-EW-Q-3-01] ; "100 Talents Project" of CAS[00000000] ; National Natural Science Foundation of China[81072580] ; National Natural Science Foundation of China[91013010] ; National Natural Science Foundation of China[21172233]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:000319446900058
出版者MDPI AG
源URL[http://119.78.100.183/handle/2S10ELR8/277633]  
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Xiong, Bing
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Zou, Yiquan,Li, Li,Chen, Wuyan,et al. Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent beta-secretase (BACE1) Inhibitors[J]. MOLECULES,2013,18(5):5706-5722.
APA Zou, Yiquan.,Li, Li.,Chen, Wuyan.,Chen, Tiantian.,Ma, Lanping.,...&Shen, Jingkang.(2013).Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent beta-secretase (BACE1) Inhibitors.MOLECULES,18(5),5706-5722.
MLA Zou, Yiquan,et al."Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent beta-secretase (BACE1) Inhibitors".MOLECULES 18.5(2013):5706-5722.

入库方式： OAI收割

来源：上海药物研究所

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