Abstract

Alzheimer’s disease is a fundamental disorder of information processing, manifesting as a chronic progressive disease affecting human memory, learning and cognition. It is a devastating disease for which no disease modifying therapeutics are available. Based upon a comprehensive series of molecular mechanics, molecular dynamics, semi-empirical and density functional theory calculations, we have modelled the interaction of beta-amyloid peptide with representative neuronal membranes. These simulations demonstrate an electrostatic anchoring of the N-terminal portion of the beta-amyloid peptide to glycosaminoglycan membrane components; the C-terminus of the peptide then destructively inserts into the neuronal membrane in a process facilitated by cholesterol rafts. Using these simulation models, we have used computer-aided drug design methods to rationally design two families of bi-aromatic compounds capable of interfering with the amyloid-membrane interaction. These small molecule compounds have been further optimized using quantitative structure-activity relationship calculations.