Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1783534204724707328 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7226079 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT coimbrajuditerm combiningvirtualscreeningprotocolandinvitroevaluationtowardsthediscoveryofbace1inhibitors AT baptistasaletej combiningvirtualscreeningprotocolandinvitroevaluationtowardsthediscoveryofbace1inhibitors AT dinisteresacp combiningvirtualscreeningprotocolandinvitroevaluationtowardsthediscoveryofbace1inhibitors AT silvamariamc combiningvirtualscreeningprotocolandinvitroevaluationtowardsthediscoveryofbace1inhibitors AT moreirapaulai combiningvirtualscreeningprotocolandinvitroevaluationtowardsthediscoveryofbace1inhibitors AT santosarmandae combiningvirtualscreeningprotocolandinvitroevaluationtowardsthediscoveryofbace1inhibitors AT salvadorjorgear combiningvirtualscreeningprotocolandinvitroevaluationtowardsthediscoveryofbace1inhibitors |