Advanced analytical methodologies in Alzheimer's disease drug discovery

Abstract

Despite the constant progress in the understanding of the etiopathogenesis of Alzheimer's disease (AD) over the last 50 years, just four long-standing drugs are currently used for AD therapy. This article reviews the analytical methodologies developed and applied in the last five years to address the early-stage tasks of the AD drug discovery process: the fast selection of active compounds (hits) and the comprehension of the ligand binding mechanism of the compound chosen to be the lead in the forthcoming development. The reviewed analytical methodologies face the most investigated pharmacological protein targets (amyloids, secretases, kinases, cholinesterases) and specific receptor- and enzyme-mediated effects in neurotransmission, neuroprotection and neurodegeneration. Some of these methodologies are noteworthy for their use in middle/high-throughput screening campaigns during hit selection (e.g. surface plasmon resonance biosensing, fluorescence resonance energy transfer assays), whereas some others (circular dichroism and nuclear magnetic resonance spectroscopies, ion mobility-mass spectrometry) can provide in-depth information about the structure, conformation and ligand binding properties of target proteins.

Keywords: Alzheimer’s disease; Amyloid beta peptide; BACE1; Cholinesterases; Mass spectrometry; Microscopies; Spectroscopies; Tau protein.