The most common type of dementia – Alzheimer's disease (AD) – is a serious neurodegenerative disorder that remains without effective pharmacological therapy to prevent the advance of the disease. The neurodegenerative process, which culminates in dementia, might be prevented through innovative disease-modifying approaches. The generation of misfolded amyloid-β (Aβ) oligomers in the AD brain is indicated in the “Amyloid Cascade Hypothesis” as the main incident underlying neurotoxic events. The Aβ peptide is produced by sequential Amyloid Precursor Protein (APP) proteolytic cleavage by β- (BACE1) and γ-secretase. Since the processing of APP by BACE1 is the crucial step in the production of Aβ, this therapeutic target has been explored for AD-modifying intervention over the past years. Thus, the main goal of this research project is the discovery of new small molecules that effectively reach the brain and inhibit BACE1. The project focuses on a reliable multiple-step protocol of virtual screening, which includes: i) a combination of a structure-based (SB) and ligand-based (LB) pharmacophore modeling to screen several druglike compound databases to identify novel anti-BACE1 agents; ii) a subsequent filter to predict their ability to cross the blood-brain barrier (BBB), a pharmacokinetic property required for these drugs; and iii) molecular docking simulations to predict the binding mode and affinity of those molecules, which enable the selection of the best candidates for further biological (in vitro and in vivo) evaluation. Moreover, while the SB approach is based on receptor-ligand key interactions of BACE1-ligand crystal complexes, the LB strategy captures the essential features of structurally diverse known active compounds that inhibit BACE1. To evaluate the quality of the developed pharmacophore models multiple metrics were calculated. Henceforth, considering simultaneously the structure of the BACE1 enzyme and the properties of the multiple active ligands, the chances of finding new compounds that effectively bind to BACE1 are enhanced.

Targeting Alzheimer's disease: A virtual screening protocol to discover new central-acting BACE1 inhibitors

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.