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Molecules 2013, 18(5), 5706-5722; doi:10.3390/molecules18055706
Article

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

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Received: 31 January 2013; in revised form: 9 April 2013 / Accepted: 9 May 2013 / Published: 16 May 2013
(This article belongs to the Section Medicinal Chemistry)
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Abstract: Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE1) is a key step in generating the N-terminal of β-amyloid (Aβ), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer’s disease. Inhibitors of BACE1 can reduce the levels of Aβ 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.
Keywords: virtual screening; docking; structure-based lead design; crystal structure; indole acylguanidine virtual screening; docking; structure-based lead design; crystal structure; indole acylguanidine
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Zou, Y.; Li, L.; Chen, W.; Chen, T.; Ma, L.; Wang, X.; Xiong, B.; Xu, Y.; Shen, J. Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) Inhibitors. Molecules 2013, 18, 5706-5722.

AMA Style

Zou Y, Li L, Chen W, Chen T, Ma L, Wang X, Xiong B, Xu Y, Shen J. Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) Inhibitors. Molecules. 2013; 18(5):5706-5722.

Chicago/Turabian Style

Zou, Yiquan; Li, Li; Chen, Wuyan; Chen, Tiantian; Ma, Lanping; Wang, Xin; Xiong, Bing; Xu, Yechun; Shen, Jingkang. 2013. "Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) Inhibitors." Molecules 18, no. 5: 5706-5722.


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