Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological Evaluations

Molecules

Zhiran Tang¹  Yingbin Yang¹  Hongyu Yang²  Xin Lu²  Yao Chen³  Li Xu⁴  Feng Wang⁴  Jifu Li⁴  Xifei Cheng⁴  You Zhou⁴  Qingyou Xia⁴ 

[1] School of Life Science, Southwest University, Chongqing 400715, China;School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China;School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China;State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing 400715, China;

关键词: alzheimer’s disease;    selective butyrylcholiesterase inhibitors;    virtual screening;    pharmacophore model;    acetylcholinesterase;    in vitro enzyme assays;   

DOI  :  10.3390/molecules24234217

来源: DOAJ

【 摘 要 】

As there are increased levels and activity of butyrylcholiesterase (BChE) in the late stage of Alzheimer’s disease (AD), development of selective BChE inhibitors is of vital importance. In this study, a workflow combining computational technologies and biological assays were implemented to identify selective BChE inhibitors with new chemical scaffolds. In particular, a pharmacophore model served as a 3D search query to screen three compound collections containing 3.0 million compounds. Molecular docking and cluster analysis were performed to increase the efficiency and accuracy of virtual screening. Finally, 15 compounds were retained for biological investigation. Results revealed that compounds 8 and 18 could potently and highly selectively inhibit BChE activities (IC₅₀ values < 10 μM on human BChE, selectivity index BChE > 30). These active compounds with novel scaffolds provided us with a good starting point to further design potent and selective BChE inhibitors, which may be beneficial for the treatment of AD.

【 授权许可】

Unknown