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Insights into the Interaction Mechanism of Ligands with A β 42 Based on Molecular Dynamics Simulations and Mechanics: Implications of Role of Common Binding Site in Drug Design for Alzheimer's Disease
Author(s) -
Kundaikar Harish S.,
Degani Mariam S.
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12555
Subject(s) - thioflavin , chemistry , biophysics , docking (animal) , molecular dynamics , curcumin , binding site , amyloid β , molecular mechanics , rational design , fibril , plasma protein binding , drug discovery , amyloid (mycology) , biochemistry , alzheimer's disease , nanotechnology , medicine , disease , biology , computational chemistry , pathology , materials science , nursing , inorganic chemistry
Aggregation of β ‐amyloid (A β ) 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 ( AV 45), with A β 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 .