Structure-based design of new N-benzyl-piperidine derivatives as multitarget-directed AChE/BuChE inhibitors for Alzheimer's disease.
acetylcholinesterase
butyrylcholinesterase
in silico toxicity
molecular dynamics
multitarget ligands
neurodegenerative disease
Journal
Journal of cellular biochemistry
ISSN: 1097-4644
Titre abrégé: J Cell Biochem
Pays: United States
ID NLM: 8205768
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
revised:
16
09
2023
received:
03
08
2023
accepted:
20
09
2023
medline:
23
11
2023
pubmed:
5
10
2023
entrez:
5
10
2023
Statut:
ppublish
Résumé
The pathogenic complexity of Alzheimer's disease (AD) demands the development of multitarget-directed agents aiming at improving actual pharmacotherapy. Based on the cholinergic hypothesis and considering the well-established role of butyrylcholinesterase (BuChE) in advanced stages of AD, the chemical structure of the acetylcholinesterase (AChE) inhibitor drug donepezil (1) was rationally modified for the design of new N-benzyl-piperidine derivatives (4a-d) as potential multitarget-direct AChE and BuChE inhibitors. The designed analogues were further studied through the integration of in silico and in vitro methods. ADMET predictions showed that 4a-d are anticipated to be orally bioavailable, able to cross the blood-brain barrier and be retained in the brain, and to have low toxicity. Computational docking and molecular dynamics indicated the formation of favorable complexes between 4a-d and both cholinesterases. Derivative 4a presented the lowest binding free energy estimation due to interaction with key residues from both target enzymes (-36.69 ± 4.47 and -32.23 ± 3.99 kcal/mol with AChE and BuChE, respectively). The in vitro enzymatic assay demonstrated that 4a was the most potent inhibitor of AChE (IC
Substances chimiques
Butyrylcholinesterase
EC 3.1.1.8
Cholinesterase Inhibitors
0
Acetylcholinesterase
EC 3.1.1.7
Piperidines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1734-1748Subventions
Organisme : Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
ID : 312878/2022-2
Organisme : Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
ID : 314723/2021-1
Organisme : Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)
ID : E-26/202.742/2019
Organisme : Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
ID : 001
Informations de copyright
© 2023 Wiley Periodicals LLC.
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