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
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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.
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.
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.