Computational Methods in the Discovery and Design of BACE-1 Inhibitors

P.      Kacker; G.      Bottegoni; A.      Cavalli

Abstract

BACE-1 is a membrane associated aspartyl protease and is one of the enzymes responsible for the hydrolysis of the amyloid precursor protein. Due to its central role in the generation of the amyloid-β peptide, it is considered as a primary drug target for Alzheimer’s disease. BACE-1 has been the focus of many drug discovery programs aimed at identifying inhibitors that effectively block this enzyme and trigger the sought therapeutic effects. Thanks to the availability of a large number of crystal structures of the catalytic domain of this enzyme, computational methods, ranging from molecular dynamics simulations, quantum mechanical calculations and ligand docking, have played a fundamental role in almost every hit discovery and hit optimization campaign performed on this target. The present article reviews the latest computational modeling and drug discovery efforts that have been carried out on this target.

Keywords: Alzheimer’s disease, BACE-1, β-site APP cleaving enzyme 1, β-secretase, protease, dyad, docking, molecular dynamics, protonation state, receptor flexibility, virtual screening.