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

doi:10.3390/molecules18055706

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	Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent beta-secretase (BACE1) Inhibitors
	Zou, Yiquan 2; Li, Li 1; Chen, Wuyan 1; Chen, Tiantian 1; Ma, Lanping2 ; Wang, Xin2 ; Xiong, Bing2 ; Xu, Yechun1 ; Shen, Jingkang 2
刊名	MOLECULES
	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
DOI	10.3390/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.
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关键词	STRUCTURE-BASED DESIGN ; X-RAY CRYSTALLOGRAPHY ; ALZHEIMERS-DISEASE ; PEPTIDOMIMETIC INHIBITORS ; THERAPEUTICS ; OPTIMIZATION ; ANTAGONISTS ; GENERATION ; PROGRESS ; PROTEIN
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
语种	英语
出版者	MDPI AG
WOS记录号	WOS:000319446900058
内容类型	期刊论文
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.