title: Anti-amyloid Aggregation Activity of Natural Compounds: Implications for Alzheimer's Drug Discovery.
abstract: Several plant-derived natural compounds are known to exhibit anti-amyloid aggregation activity which makes them attractive as potential therapies to treat Alzheimer's disease. The mechanisms of their anti-amyloid activity are not well known. In this regard, many natural compounds are known to exhibit direct binding to various amyloid species including oligomers and fibrils, which in turn can lead to conformational change in the beta-sheet assembly to form nontoxic aggregates. This review discusses the mechanism of anti-amyloid activity of 16 natural compounds and gives structural details on their direct binding interactions with amyloid aggregates. Our computational investigations show that the physicochemical properties of natural products do fit Lipinski's criteria and that catechol and catechol-type moieties present in natural compounds act as lysine site-specific inhibitors of amyloid aggregation. Based on these observations, we propose a structural template to design novel small molecules containing site-specific ring scaffolds, planar aromatic and nonaromatic linkers with suitably substituted hydrogen bond acceptors and donors. These studies will have significant implications in the design and development of novel amyloid aggregation inhibitors with superior metabolic stability and blood-brain barrier penetration as potential agents to treat Alzheimer's disease.
authors.affiliation: Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, China.
authors.forename: Xian-Le
authors.initials: XL
authors.lastname: Bu
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada. praopera@uwaterloo.ca.
authors.forename: Praveen P N
authors.initials: PPN
authors.lastname: Rao
authors.affiliation: Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, China. yanjiang_wang@tmmu.edu.cn.
authors.forename: Yan-Jiang
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001688:Biological Products / Q000494:pharmacology / Q000627:therapeutic use*; D019295:Computational Biology; D055808:Drug Discovery; D006801:Humans; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D001688:Biological Products
keywords: Alzheimer’s disease; Beta-amyloid; Molecular docking; Natural compounds; Pharmacophore modeling