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Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-A beta Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation

文献类型：期刊论文

作者Jiang, Cheng-Shi1; Ge, Yong-Xi1; Cheng, Zhi-Qiang1; Wang, Yin-Yin1; Tao, Hong-Rui1,2; Zhu, Kongkai1; Zhang, Hua1
刊名MOLECULES
出版日期2019-07-02
卷号24期号:14页码:21
关键词selective BChE inhibitor virtual screening structural optimization molecular dynamics anti-A beta aggregation
DOI10.3390/molecules24142568
通讯作者Jiang, Cheng-Shi(bio_jiangcs@ujn.edu.cn) ; Zhu, Kongkai(zhukk@ujn.edu.cn) ; Zhang, Hua(bio_zhangh@ujn.edu.cn)
英文摘要In this study, a series of selective butyrylcholinesterase (BChE) inhibitors was designed and synthesized from the structural optimization of hit 1, a 4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzoic acid derivative identified by virtual screening our compound library. The in vitro enzyme assay results showed that compounds 9 ((4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone) and 23 (N-(2-bromophenyl)-4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzamide) displayed improved BChE inhibitory activity and good selectivity towards BChE versus AChE. Their binding modes were probed by molecular docking and further validated by molecular dynamics simulation. Kinetic analysis together with molecular modeling studies suggested that these derivatives could target both the catalytic active site (CAS) and peripheral anionic site (PAS) of BChE. In addition, the selected compounds 9 and 23 displayed anti-A beta(1-42) aggregation activity in a dose-dependent manner, and they did not show obvious cytotoxicity towards SH-SY5Y neuroblastoma cells. Also, both compounds showed significantly protective activity against A beta(1-42)-induced toxicity in a SH-SY5Y cell model. The present results provided a new valuable chemical template for the development of selective BChE inhibitors.
WOS关键词MOLECULAR-DYNAMICS ; ACETYLCHOLINESTERASE INHIBITORS ; ALZHEIMERS-DISEASE ; POTENT INHIBITORS ; ACCURATE DOCKING ; DRUG DEVELOPMENT ; DERIVATIVES ; DESIGN ; GLIDE ; MODEL
资助项目National Natural Science Foundation of China[21672082] ; National Natural Science Foundation of China[81803438] ; Natural Science Foundation of Shandong Province[ZR2019YQ31] ; Natural Science Foundation of Shandong Province[ZR2017BH038] ; Natural Science Foundation of Shandong Province[JQ201721] ; Natural Science Foundation of Shandong Province[ZR2018ZC0944] ; Young Taishan Scholars Program[tsqn20161037] ; Shandong Talents Team Cultivation Plan of University Preponderant Discipline[10027]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:000482303000051
出版者MDPI
源URL[http://119.78.100.183/handle/2S10ELR8/288720]  
专题新药研究国家重点实验室
通讯作者Jiang, Cheng-Shi; Zhu, Kongkai; Zhang, Hua
作者单位1.Univ Jinan, Sch Biol Sci & Technol, Jinan 250022, Shandong, Peoples R China
2.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Meteria Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Jiang, Cheng-Shi,Ge, Yong-Xi,Cheng, Zhi-Qiang,et al. Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-A beta Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation[J]. MOLECULES,2019,24(14):21.
APA Jiang, Cheng-Shi.,Ge, Yong-Xi.,Cheng, Zhi-Qiang.,Wang, Yin-Yin.,Tao, Hong-Rui.,...&Zhang, Hua.(2019).Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-A beta Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation.MOLECULES,24(14),21.
MLA Jiang, Cheng-Shi,et al."Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-A beta Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation".MOLECULES 24.14(2019):21.

入库方式： OAI收割

来源：上海药物研究所

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