Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening.
Molecules
; 26(7)2021 Apr 03.
Article
em En
| MEDLINE
| ID: mdl-33916760
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Interface Usuário-Computador
/
Desenho de Fármacos
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Inibidores da Colinesterase
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Avaliação Pré-Clínica de Medicamentos
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Descoberta de Drogas
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
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Screening_studies
Limite:
Animals
Idioma:
En
Revista:
Molecules
Assunto da revista:
BIOLOGIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Bulgária