Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors

Biomolecules

ArmandaE. Santos¹  PaulaI. Moreira¹  SaleteJ. Baptista¹  TeresaC. P. Dinis¹  JorgeA. R. Salvador²  MariaM. C. Silva²  JuditeR. M. Coimbra² 

[1] Center for Innovative Biomedicine and Biotechnology (CIBB), Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal;Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal;

关键词: Alzheimer’s disease (AD);    amyloid-β (Aβ);    BACE1;    small bioactive molecules;    virtual screening;    pharmacophore modelling;   

DOI  :  10.3390/biom10040535

来源: DOAJ

【 摘 要 】

The treatment options for a patient diagnosed with Alzheimer’s disease (AD) are currently limited. The cerebral accumulation of amyloid-β (Aβ) is a critical molecular event in the pathogenesis of AD. When the amyloidogenic β-secretase (BACE1) is inhibited, the production of Aβ peptide is reduced. Henceforth, the main goal of this study is the discovery of new small bioactive molecules that potentially reach the brain and inhibit BACE1. The work was conducted by a customized molecular modelling protocol, including pharmacophore-based and molecular docking-based virtual screening (VS). Structure-based (SB) and ligand-based (LB) pharmacophore models were designed to accurately screen several drug-like compound databases. The retrieved hits were subjected to molecular docking and in silico filtered to predict their ability to cross the blood–brain barrier (BBB). Additionally, 34 high-scoring compounds structurally distinct from known BACE1 inhibitors were selected for in vitro screening assay, which resulted in 13 novel hit-compounds for this relevant therapeutic target. This study disclosed new BACE1 inhibitors, proving the utility of combining computational and in vitro approaches for effectively predicting anti-BACE1 agents in the early drug discovery process.

【 授权许可】

Unknown