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

Molecules. 2019 Jul 15;24(14):2568. doi: 10.3390/molecules24142568.

Abstract

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.

Keywords: anti-Aβ aggregation; molecular dynamics; selective BChE inhibitor; structural optimization; virtual screening.

MeSH terms

  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Benzoates / chemical synthesis*
  • Benzoates / chemistry
  • Benzoates / pharmacology
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism*
  • Catalytic Domain / drug effects
  • Cell Line, Tumor
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Phenols
  • Protein Aggregates / drug effects
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Benzoates
  • Cholinesterase Inhibitors
  • Phenols
  • Protein Aggregates
  • Butyrylcholinesterase