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

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. He...

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Autores principales: Coimbra, Judite R. M., Baptista, Salete J., Dinis, Teresa C. P., Silva, Maria M. C., Moreira, Paula I., Santos, Armanda E., Salvador, Jorge A. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226079/
https://www.ncbi.nlm.nih.gov/pubmed/32244832
http://dx.doi.org/10.3390/biom10040535
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author Coimbra, Judite R. M.
Baptista, Salete J.
Dinis, Teresa C. P.
Silva, Maria M. C.
Moreira, Paula I.
Santos, Armanda E.
Salvador, Jorge A. R.
author_facet Coimbra, Judite R. M.
Baptista, Salete J.
Dinis, Teresa C. P.
Silva, Maria M. C.
Moreira, Paula I.
Santos, Armanda E.
Salvador, Jorge A. R.
author_sort Coimbra, Judite R. M.
collection PubMed
description 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.
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spelling pubmed-72260792020-05-18 Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors Coimbra, Judite R. M. Baptista, Salete J. Dinis, Teresa C. P. Silva, Maria M. C. Moreira, Paula I. Santos, Armanda E. Salvador, Jorge A. R. Biomolecules Article 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. MDPI 2020-04-01 /pmc/articles/PMC7226079/ /pubmed/32244832 http://dx.doi.org/10.3390/biom10040535 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Coimbra, Judite R. M.
Baptista, Salete J.
Dinis, Teresa C. P.
Silva, Maria M. C.
Moreira, Paula I.
Santos, Armanda E.
Salvador, Jorge A. R.
Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors
title Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors
title_full Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors
title_fullStr Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors
title_full_unstemmed Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors
title_short Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors
title_sort combining virtual screening protocol and in vitro evaluation towards the discovery of bace1 inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226079/
https://www.ncbi.nlm.nih.gov/pubmed/32244832
http://dx.doi.org/10.3390/biom10040535
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