In Silico Strategies to Design Small Molecules to Study Beta-Amyloid Aggregation

Abstract

The amyloid cascade hypothesis of Alzheimer’s disease is an intriguing and complex pathway which alludes to the accumulation of amyloid (Aβ) aggregates as a key toxic event. In this regard, computational tools can be effectively used to study and design amyloid aggregation inhibitors and modulators. A number of in silico methods have been described in the literature, which use full-length Aβ proteins. However, these methods are computationally expensive. Herein, we describe an in silico method that uses the Aβ hexapeptide-derived steric-zipper octamer assembly as an alternative and effective model to predict the binding interactions of planar small molecule libraries with complex Aβ structures including oligomers, protofibrils, and fibrils. The method provides detailed steps involved in conducting molecular docking, the interpretation of results obtained including ligand-Aβ hexapeptide interactions, calculation of ligand binding energies, and its correlation with the ligand binding affinity. This octamer steric-zipper model represents a relevant prototype to explore and study the mechanisms of Aβ aggregation using small molecules.