AUTHOR=Mohamed Yusof Nur Intan Saidaah , Abdullah Zafirah Liyana , Othman Norodiyah , Mohd Fauzi Fazlin TITLE=Structure–Activity Relationship Analysis of Flavonoids and Its Inhibitory Activity Against BACE1 Enzyme Toward a Better Therapy for Alzheimer’s Disease JOURNAL=Frontiers in Chemistry VOLUME=10 YEAR=2022 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2022.874615 DOI=10.3389/fchem.2022.874615 ISSN=2296-2646 ABSTRACT=
Drug development in Alzheimer’s disease (AD) suffers from a high attrition rate. In 2021, 117 agents tested in phases I and II and 36 agents tested in phase III were discontinued. Natural product compounds may be good lead compounds for AD as they contain functional groups that are important for binding against key AD targets such as β-secretase enzyme (BACE1). Hence, in this study, 64 flavonoids collected from rigorous literature search and screening that have been tested from 2010 to 2022 against BACE1, which interferes in the formation of amyloid plaque, were analyzed. The 64 unique flavonoids can be further classified into five core fragments. The flavonoids were subjected to clustering analysis based on its structure, and each representative of the clusters was subjected to molecular docking. There were 12 clusters formed, where only 1 cluster contained compounds from two different core fragments. Several observations can be made where 1) flavanones with sugar moieties showed higher inhibitory activity compared to flavanones without sugar moieties. The number of sugar moieties and position of glycosidic linkage may also affect the inhibitory activity. 2) Non-piperazine-substituted chalcones when substituted with functional groups with decreasing electronegativity at the