Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-Aβ Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation
Copyright policy )Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-Aβ Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation
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-Aβ1–42 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 Aβ1-42-induced toxicity in a SH-SY5Y cell model. The present results provided a new valuable chemical template for the development of selective BChE inhibitors.
- Chinese Academy of Science (中国科学院) China (People's Republic of)
- Chinese Academy of Science China (People's Republic of)
- University of Jinan China (People's Republic of)
- State Key Laboratory of Drug Research China (People's Republic of)
- Chinese Academy of Sciences (中国科学院) China (People's Republic of)
Models, Molecular, Organic chemistry, Molecular Dynamics Simulation, Benzoates, Article, Protein Aggregates, Structure-Activity Relationship, QD241-441, selective BChE inhibitor, Phenols, Catalytic Domain, Cell Line, Tumor, Humans, structural optimization, anti-Aβ aggregation, Amyloid beta-Peptides, Dose-Response Relationship, Drug, Molecular Structure, virtual screening, molecular dynamics, Molecular Docking Simulation, Butyrylcholinesterase, Drug Design, Cholinesterase Inhibitors
Models, Molecular, Organic chemistry, Molecular Dynamics Simulation, Benzoates, Article, Protein Aggregates, Structure-Activity Relationship, QD241-441, selective BChE inhibitor, Phenols, Catalytic Domain, Cell Line, Tumor, Humans, structural optimization, anti-Aβ aggregation, Amyloid beta-Peptides, Dose-Response Relationship, Drug, Molecular Structure, virtual screening, molecular dynamics, Molecular Docking Simulation, Butyrylcholinesterase, Drug Design, Cholinesterase Inhibitors
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