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Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) Inhibitors
- Source :
- Molecules, Vol 18, Iss 5, Pp 5706-5722 (2013)
- Publication Year :
- 2013
- Publisher :
- MDPI AG, 2013.
-
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.
Details
- Language :
- English
- ISSN :
- 14203049
- Volume :
- 18
- Issue :
- 5
- Database :
- Directory of Open Access Journals
- Journal :
- Molecules
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.8bfcb918433f4a25985439a8b80caff8
- Document Type :
- article
- Full Text :
- https://doi.org/10.3390/molecules18055706