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Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening

Despite extensive and intensive research efforts in recent decades, there is still no effective treatment for neurodegenerative diseases. On this background, the use of drugs inhibiting the enzyme acetylcholinesterase (AChE) remains an eternal evergreen in the symptomatic treatment of mild to modera...

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Autores principales: Stavrakov, Georgi, Philipova, Irena, Lukarski, Atanas, Atanasova, Mariyana, Georgiev, Borislav, Atanasova, Teodora, Konstantinov, Spiro, Doytchinova, Irini
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038331/
https://www.ncbi.nlm.nih.gov/pubmed/33916760
http://dx.doi.org/10.3390/molecules26072058
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author Stavrakov, Georgi
Philipova, Irena
Lukarski, Atanas
Atanasova, Mariyana
Georgiev, Borislav
Atanasova, Teodora
Konstantinov, Spiro
Doytchinova, Irini
author_facet Stavrakov, Georgi
Philipova, Irena
Lukarski, Atanas
Atanasova, Mariyana
Georgiev, Borislav
Atanasova, Teodora
Konstantinov, Spiro
Doytchinova, Irini
author_sort Stavrakov, Georgi
collection PubMed
description Despite extensive and intensive research efforts in recent decades, there is still no effective treatment for neurodegenerative diseases. On this background, the use of drugs inhibiting the enzyme acetylcholinesterase (AChE) remains an eternal evergreen in the symptomatic treatment of mild to moderate cognitive impairments. Even more, the cholinergic hypothesis, somewhat forgotten in recent years due to the shift in focus on amyloid cascade, is back to life, and the search for new, more effective AChE inhibitors continues. We generated a fragment-based library containing aromatic moieties and linkers originating from a set of novel AChE inhibitors. We used this library to design 1220 galantamine (GAL) derivatives following the model GAL (binding core) - linker (L) - aromatic fragment (Ar). The newly designed compounds were screened virtually for blood–brain barrier (BBB) permeability and binding to AChE. Among the top 10 best-scored compounds, a representative lead molecule was selected and tested for anti-AChE activity and neurotoxicity. It was found that the selected compound was a powerful non-toxic AChE inhibitor, 68 times more active than GAL, and could serve as a lead molecule for further optimization and development.
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spelling pubmed-80383312021-04-12 Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening Stavrakov, Georgi Philipova, Irena Lukarski, Atanas Atanasova, Mariyana Georgiev, Borislav Atanasova, Teodora Konstantinov, Spiro Doytchinova, Irini Molecules Article Despite extensive and intensive research efforts in recent decades, there is still no effective treatment for neurodegenerative diseases. On this background, the use of drugs inhibiting the enzyme acetylcholinesterase (AChE) remains an eternal evergreen in the symptomatic treatment of mild to moderate cognitive impairments. Even more, the cholinergic hypothesis, somewhat forgotten in recent years due to the shift in focus on amyloid cascade, is back to life, and the search for new, more effective AChE inhibitors continues. We generated a fragment-based library containing aromatic moieties and linkers originating from a set of novel AChE inhibitors. We used this library to design 1220 galantamine (GAL) derivatives following the model GAL (binding core) - linker (L) - aromatic fragment (Ar). The newly designed compounds were screened virtually for blood–brain barrier (BBB) permeability and binding to AChE. Among the top 10 best-scored compounds, a representative lead molecule was selected and tested for anti-AChE activity and neurotoxicity. It was found that the selected compound was a powerful non-toxic AChE inhibitor, 68 times more active than GAL, and could serve as a lead molecule for further optimization and development. MDPI 2021-04-03 /pmc/articles/PMC8038331/ /pubmed/33916760 http://dx.doi.org/10.3390/molecules26072058 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Stavrakov, Georgi
Philipova, Irena
Lukarski, Atanas
Atanasova, Mariyana
Georgiev, Borislav
Atanasova, Teodora
Konstantinov, Spiro
Doytchinova, Irini
Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening
title Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening
title_full Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening
title_fullStr Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening
title_full_unstemmed Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening
title_short Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening
title_sort discovery of a novel acetylcholinesterase inhibitor by fragment-based design and virtual screening
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038331/
https://www.ncbi.nlm.nih.gov/pubmed/33916760
http://dx.doi.org/10.3390/molecules26072058
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