Design of Curcumin and Flavonoid Derivatives with Acetylcholinesterase and Beta-Secretase Inhibitory Activities Using in Silico Approaches

Molecules

Thai-Son Tran¹  Minh-Tri Le¹  Khac-Minh Thai¹  Thanh-Dao Tran¹  The-Huan Tran² 

[1] Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam;Department of Pharmaceutical Chemistry, Faculty of Pharmacy, College of Medicine and Pharmacy, Hue University, Hue City 530000, Vietnam;

关键词: acetylcholinesterase;    beta-secretase;    curcumin;    flavonoid;    in silico;   

DOI  :  10.3390/molecules25163644

来源: DOAJ

【 摘 要 】

Acetylcholinesterase (AChE) and beta-secretase (BACE-1) are the two crucial enzymes involved in the pathology of Alzheimer’s disease. The former is responsible for many defects in cholinergic signaling pathway and the latter is the primary enzyme in the biosynthesis of beta-amyloid as the main component of the amyloid plaques. These both abnormalities are found in the brains of Alzheimer’s patients. In this study, in silico models were developed, including 3D-pharmacophore, 2D-QSAR (two-dimensional quantitative structure-activity relationship), and molecular docking, to screen virtually a database of compounds for AChE and BACE-1 inhibitory activities. A combinatorial library containing more than 3 million structures of curcumin and flavonoid derivatives was generated and screened for drug-likeness and enzymatic inhibitory bioactivities against AChE and BACE-1 through the validated in silico models. A total of 47 substances (two curcumins and 45 flavonoids), with remarkable predicted pIC₅₀ values against AChE and BACE-1 ranging from 4.24–5.11 (AChE) and 4.52–10.27 (BACE-1), were designed. The in vitro assays on AChE and BACE-1 were performed and confirmed the in silico results. The study indicated that, by using in silico methods, a series of curcumin and flavonoid structures were generated with promising predicted bioactivities. This would be a helpful foundation for the experimental investigations in the future. Designed compounds which were the most feasible for chemical synthesis could be potential candidates for further research and lead optimization.

【 授权许可】

Unknown