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

Cheng-Shi Jiang,Zhi-Qiang Cheng,Kongkai Zhu,Yong-Xi Ge,Hua Zhang,Yin-Yin Wang,Hong-Rui Tao

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.

Highlights

Alzheimer’s disease (AD), one of the most common neurodegenerative disorders, accounts for about 60–80% of all cases of dementia [1,2]
The BChE protein coordinates were first processed with the Protein Preparation Wizard Workflow inserted in Maestro, coordinates were first processed with the Protein Preparation Wizard Workflow inserted in Maestro, and the default settings were used for this step
A series of novel selective BChE inhibitors were derived from the structural optimization of hit 1

Summary

Introduction

Alzheimer’s disease (AD), one of the most common neurodegenerative disorders, accounts for about 60–80% of all cases of dementia [1,2]. Nearly 50 million people worldwide have AD or a related dementia, and the number of AD patients is expected to triple by 2050 [3]. There is still no successful therapy or drug to reverse or even slow the course of this disease [5]. The pathogenesis of AD is complex and not fully understood, several important clinical hallmarks, such as low level of acetylcholine (ACh), beta-amyloid (Aβ) protein aggregation, and tau (τ)-protein phosphorylation, are involved in the occurrence and development of AD [6]. Therapies for anti-AD primarily focused on Aβ and tau have received more attention [7], Molecules 2019, 24, 2568; doi:10.3390/molecules24142568 www.mdpi.com/journal/molecules

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Results

Conclusion