Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors
| Autor: | Armanda E. Santos, Paula I. Moreira, M. Manuel Cruz Silva, Salete J. Baptista, Jorge A. R. Salvador, Judite R M Coimbra, Teresa C.P. Dinis |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
structure- and ligand-based methods
Protein Conformation Bioactive molecules In silico lcsh:QR1-502 Drug Evaluation Preclinical small bioactive molecules Alzheimer’s disease (AD) Computational biology Ligands Biochemistry lcsh:Microbiology Article 03 medical and health sciences User-Computer Interface 0302 clinical medicine mental disorders Protease Inhibitors Molecular Biology 030304 developmental biology 0303 health sciences Virtual screening pharmacophore modelling Drug discovery Chemistry amyloid-β (Aβ) Screening assay Treatment options BACE1 molecular docking virtual screening In vitro Molecular Docking Simulation Blood-Brain Barrier Pharmacophore Amyloid Precursor Protein Secretases 030217 neurology & neurosurgery |
| Zdroj: | Biomolecules Volume 10 Issue 4 Biomolecules, Vol 10, Iss 535, p 535 (2020) |
| ISSN: | 2218-273X |
| DOI: | 10.3390/biom10040535 |
| Popis: | The treatment options for a patient diagnosed with Alzheimer&rsquo s disease (AD) are currently limited. The cerebral accumulation of amyloid-&beta (A&beta ) is a critical molecular event in the pathogenesis of AD. When the amyloidogenic &beta secretase (BACE1) is inhibited, the production of A&beta 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&ndash 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. |
| Databáze: | OpenAIRE |
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