title: Insights into the Interaction Mechanism of Ligands with Aβ42 Based on Molecular Dynamics Simulations and Mechanics: Implications of Role of Common Binding Site in Drug Design for Alzheimer's Disease.
abstract: Aggregation of β-amyloid (Aβ) into oligomers and further into fibrils is hypothesized to be a key factor in pathology of Alzheimer's disease (AD). In this study, mapping and docking were used to study the binding of ligands to protofibrils. It was followed by molecular simulations to understand the differences in interactions of known therapeutic agents such as curcumin, fluorescence-based amyloid staining agents such as thioflavin T, and diagnostic agents such as florbetapir (AV45), with Aβ protofibrils. We show that therapeutic agents bind to and distort the protofibrils, thus causing destabilization or prevention of oligomerization, in contrast to diagnostic agents which bind to but do not distort such structures. This has implications in the rational design of ligands, both for diagnostics and therapeutics of AD.
authors.affiliation: Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Mumbai, 400 019, India.
authors.forename: Harish S
authors.initials: HS
authors.lastname: Kundaikar
authors.affiliation: Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Mumbai, 400 019, India.
authors.forename: Mariam S
authors.initials: MS
authors.lastname: Degani
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D000682:Amyloid / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D008024:Ligands; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Aβ42; curcumin; docking; drug design; florbetapir; molecular mechanics; molecular simulation; thioflavin T