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

doi:10.3390/molecules24142568

	Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-A beta Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation
	Jiang, Cheng-Shi 1; Ge, Yong-Xi 1; Cheng, Zhi-Qiang 1; Wang, Yin-Yin 1; Tao, Hong-Rui 1,2; Zhu, Kongkai 1; Zhang, Hua 1
刊名	MOLECULES
	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
DOI	10.3390/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.
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关键词	MOLECULAR-DYNAMICS ; ACETYLCHOLINESTERASE INHIBITORS ; ALZHEIMERS-DISEASE ; POTENT INHIBITORS ; ACCURATE DOCKING ; DRUG DEVELOPMENT ; DERIVATIVES ; DESIGN ; GLIDE ; MODEL
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
语种	英语
出版者	MDPI
WOS记录号	WOS:000482303000051
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/288720]
专题	中国科学院上海药物研究所
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.