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

Judite R M Coimbra,Armanda E Santos,Paula I Moreira,Maria M C Silva,Jorge A R Salvador,Salete J Baptista,Teresa C P Dinis

doi:10.3390/biom10040535

Judite R M Coimbra, Armanda E Santos + Show 5 more

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https://doi.org/10.3390/biom10040535

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Journal: Biomolecules	Publication Date: Apr 1, 2020
Citations: 12	License type: CC BY 4.0

Affiliation: University of Coimbra

Abstract

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.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder that massively alters the mental capacity of patients suffering from this condition
The formation of Aβ peptide requires the initial cleavage of Amyloid Precursor Protein (APP) by the transmembrane aspartyl protease BACE1 (β-site APP cleaving enzyme 1), which is one of the major therapeutic targets being currently explored for an AD-modifying intervention
In order to reach the brain, the inhibitors need to cross the blood–brain barrier (BBB) and neuronal membranes, a clear strategy to target BACE1 is based on small molecules, which are more prone to exhibiting a broad range of suitable drug-like properties [8]

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder that massively alters the mental capacity of patients suffering from this condition. The neurodegenerative process is associated with extensive neurotransmission deficits and neuronal function impairment in cerebral areas essential to cognitive processes, being responsible for the clinical manifestation of dementia [1]. It is important to pursue the development of disease-modifying therapies acting the main targets involved in the disease’s pathogenesis allowing to slow the development of structural and functional abnormalities in the central nervous system (CNS), which could potentially provide sustainable improvements of cognitive functions [4]. The cerebral accumulation of the misfolded amyloid-β (Aβ) oligomers have been indicated as the main incident underlying neurotoxic events in AD [5]. BACE1 inhibition is recognized worldwide as a potential strategy in decreasing Aβ neurotoxic concentrations [6], the development of effective BACE1 inhibitors has been a demanding process [7]. In order to reach the brain, the inhibitors need to cross the blood–brain barrier (BBB) and neuronal membranes, a clear strategy to target BACE1 is based on small molecules, which are more prone to exhibiting a broad range of suitable drug-like properties [8]

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