Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological Evaluations
As there are increased levels and activity of butyrylcholiesterase (BChE) in the late stage of Alzheimer’s disease (AD), development of selective BChE inhibitors is of vital importance. In this study, a workflow combining computational technologies and biological assays were implemented to...
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MDPI AG
2019-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/23/4217 |
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| author | You Zhou Xin Lu Hongyu Yang Yao Chen Feng Wang Jifu Li Zhiran Tang Xifei Cheng Yingbin Yang Li Xu Qingyou Xia |
| author_facet | You Zhou Xin Lu Hongyu Yang Yao Chen Feng Wang Jifu Li Zhiran Tang Xifei Cheng Yingbin Yang Li Xu Qingyou Xia |
| author_sort | You Zhou |
| collection | DOAJ |
| description | As there are increased levels and activity of butyrylcholiesterase (BChE) in the late stage of Alzheimer’s disease (AD), development of selective BChE inhibitors is of vital importance. In this study, a workflow combining computational technologies and biological assays were implemented to identify selective BChE inhibitors with new chemical scaffolds. In particular, a pharmacophore model served as a 3D search query to screen three compound collections containing 3.0 million compounds. Molecular docking and cluster analysis were performed to increase the efficiency and accuracy of virtual screening. Finally, 15 compounds were retained for biological investigation. Results revealed that compounds <strong>8</strong> and <strong>18</strong> could potently and highly selectively inhibit BChE activities (IC<sub>50</sub> values < 10 μM on human BChE, selectivity index BChE > 30). These active compounds with novel scaffolds provided us with a good starting point to further design potent and selective BChE inhibitors, which may be beneficial for the treatment of AD. |
| first_indexed | 2024-12-11T09:12:58Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-11T09:12:58Z |
| publishDate | 2019-11-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj.art-d132269ecf1d49f1a98a553dd3ff2f562022-12-22T01:13:27ZengMDPI AGMolecules1420-30492019-11-012423421710.3390/molecules24234217molecules24234217Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological EvaluationsYou Zhou0Xin Lu1Hongyu Yang2Yao Chen3Feng Wang4Jifu Li5Zhiran Tang6Xifei Cheng7Yingbin Yang8Li Xu9Qingyou Xia10State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing 400715, ChinaSchool of Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaSchool of Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaSchool of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaState Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing 400715, ChinaState Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing 400715, ChinaSchool of Life Science, Southwest University, Chongqing 400715, ChinaState Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing 400715, ChinaSchool of Life Science, Southwest University, Chongqing 400715, ChinaState Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing 400715, ChinaState Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing 400715, ChinaAs there are increased levels and activity of butyrylcholiesterase (BChE) in the late stage of Alzheimer’s disease (AD), development of selective BChE inhibitors is of vital importance. In this study, a workflow combining computational technologies and biological assays were implemented to identify selective BChE inhibitors with new chemical scaffolds. In particular, a pharmacophore model served as a 3D search query to screen three compound collections containing 3.0 million compounds. Molecular docking and cluster analysis were performed to increase the efficiency and accuracy of virtual screening. Finally, 15 compounds were retained for biological investigation. Results revealed that compounds <strong>8</strong> and <strong>18</strong> could potently and highly selectively inhibit BChE activities (IC<sub>50</sub> values < 10 μM on human BChE, selectivity index BChE > 30). These active compounds with novel scaffolds provided us with a good starting point to further design potent and selective BChE inhibitors, which may be beneficial for the treatment of AD.https://www.mdpi.com/1420-3049/24/23/4217alzheimer’s diseaseselective butyrylcholiesterase inhibitorsvirtual screeningpharmacophore modelacetylcholinesterasein vitro enzyme assays |
| spellingShingle | You Zhou Xin Lu Hongyu Yang Yao Chen Feng Wang Jifu Li Zhiran Tang Xifei Cheng Yingbin Yang Li Xu Qingyou Xia Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological Evaluations Molecules alzheimer’s disease selective butyrylcholiesterase inhibitors virtual screening pharmacophore model acetylcholinesterase in vitro enzyme assays |
| title | Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological Evaluations |
| title_full | Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological Evaluations |
| title_fullStr | Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological Evaluations |
| title_full_unstemmed | Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological Evaluations |
| title_short | Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological Evaluations |
| title_sort | discovery of selective butyrylcholinesterase bche inhibitors through a combination of computational studies and biological evaluations |
| topic | alzheimer’s disease selective butyrylcholiesterase inhibitors virtual screening pharmacophore model acetylcholinesterase in vitro enzyme assays |
| url | https://www.mdpi.com/1420-3049/24/23/4217 |
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