Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) Inhibitors
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2013-05-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | http://www.mdpi.com/1420-3049/18/5/5706 |
| _version_ | 1818927379802750976 |
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| author | Bing Xiong Yechun Xu Jingkang Shen Xin Wang Lanping Ma Tiantian Chen Wuyan Chen Yiquan Zou Li Li |
| author_facet | Bing Xiong Yechun Xu Jingkang Shen Xin Wang Lanping Ma Tiantian Chen Wuyan Chen Yiquan Zou Li Li |
| author_sort | Bing Xiong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T03:12:05Z |
| format | Article |
| id | doaj.art-8bfcb918433f4a25985439a8b80caff8 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-20T03:12:05Z |
| publishDate | 2013-05-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj.art-8bfcb918433f4a25985439a8b80caff82022-12-21T19:55:25ZengMDPI AGMolecules1420-30492013-05-011855706572210.3390/molecules18055706Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) InhibitorsBing XiongYechun XuJingkang ShenXin WangLanping MaTiantian ChenWuyan ChenYiquan ZouLi LiProteolytic 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.http://www.mdpi.com/1420-3049/18/5/5706virtual screeningdockingstructure-based lead designcrystal structureindole acylguanidine |
| spellingShingle | Bing Xiong Yechun Xu Jingkang Shen Xin Wang Lanping Ma Tiantian Chen Wuyan Chen Yiquan Zou Li Li Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) Inhibitors Molecules virtual screening docking structure-based lead design crystal structure indole acylguanidine |
| title | Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) Inhibitors |
| title_full | Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) Inhibitors |
| title_fullStr | Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) Inhibitors |
| title_full_unstemmed | Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) Inhibitors |
| title_short | Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) Inhibitors |
| title_sort | virtual screening and structure based discovery of indole acylguanidines as potent β secretase bace1 inhibitors |
| topic | virtual screening docking structure-based lead design crystal structure indole acylguanidine |
| url | http://www.mdpi.com/1420-3049/18/5/5706 |
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