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

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 16; p. 3644
• Main Authors: Tran, Thai-Son, Le, Minh-Tri, Tran, Thanh-Dao, Tran, The-Huan, Thai, Khac-Minh
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.08.2020; MDPI
• Subjects: Abnormalities; Acetylcholinesterase; Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Alzheimer's disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; beta-secretase; Binding Sites; Biological activity; Biosynthesis; Brain; Chemical synthesis; Cholinergics; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - metabolism; Combinatorial analysis; Curcumin; Curcumin - chemistry; Curcumin - metabolism; Databases, Chemical; Dementia; Design; Drug Design; Enzymes; flavonoid; Flavonoids; Flavonoids - chemistry; Flavonoids - metabolism; Humans; Hydrogen Bonding; in silico; Inhibitory Concentration 50; Libraries; Ligands; Molecular docking; Molecular Docking Simulation; Molecular structure; Optimization; Plaques; Protease Inhibitors - chemistry; Protease Inhibitors - metabolism; Quantitative Structure-Activity Relationship; Secretase; Signal transduction; Software; Structure-activity relationships; Two dimensional models; β-Amyloid; β-Site APP-cleaving enzyme 1; β-Site APP-cleaving enzymes; acetylcholinesterase; flavonoid; in silico; beta-secretase; curcumin
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25163644

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 pIC 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.