Pharmacophore mapping of the crucial mediators of acetylcholinesterase and butyrylcholinesterase dual inhibition in Alzheimer's disease.
Mol Divers
; 26(5): 2761-2774, 2022 Oct.
Article
en En
| MEDLINE
| ID: mdl-35067751
ABSTRACT
Optimization and re-optimization of bioactive molecules using in silico methods have found application in the design of more active ones. Herein, we applied a pharmacophore modeling approach to screen potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) aimed at Alzheimer's disease (AD) treatment. The investigation entails molecular dynamics simulation, docking, pharmacophore modeling, drug-like screening, and binding energy analysis. We prepared a pharmacophore model from approved inhibitors of AChE and BuChE to predict the crucial moieties required for optimum molecular interaction with these proteins. The obtained pharmacophore model, used for database screening via some critical criteria, showed 229 hit molecules. Further analyses showed 42 likely dual inhibitors of AChE/BuChE with drug-like and pharmacokinetics properties the same as the approved cholinesterase inhibitors. Finally, we identified 14 dual molecules with improved potentials over the existing inhibitors and simulated ZINC92385797 bound to human AChE and BuChE structure after noticing that these 14 molecules are similar. The selected compound maintained relative stability at the active sites of both proteins over 120 ns simulation. Our integrated protocols showed the pertinent recipes of anti-AD drug design through the in silico pipeline.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Acetilcolinesterasa
/
Enfermedad de Alzheimer
Tipo de estudio:
Guideline
/
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Mol Divers
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2022
Tipo del documento:
Article
País de afiliación:
Sudáfrica