Structure-based design of new N-benzyl-piperidine derivatives as multitarget-directed AChE/BuChE inhibitors for Alzheimer's disease

• Published in: Journal of cellular biochemistry Vol. 124; no. 11; pp. 1734 - 1748
• Main Authors: Conceição, Raissa Alves da, von Ranke, Natalia, Azevedo, Luciana, Franco, Daiana, Nadur, Nathalia Fonseca, Kummerle, Arthur Eugen, Barbosa, Maria Letícia de C, Souza, Alessandra M T
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.11.2023
• Subjects: Acetylcholinesterase; Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Bioavailability; Blood-brain barrier; Brain; Butyrylcholinesterase - metabolism; Butyrylcholinesterase - therapeutic use; Cholinergics; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Computational neuroscience; Donepezil; Drug development; Drug therapy; Free energy; Humans; In vitro methods and tests; Inhibitors; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Neurodegenerative diseases; Piperidine; Piperidines - pharmacology; Piperidines - therapeutic use; Structure-Activity Relationship; Toxicity; acetylcholinesterase; butyrylcholinesterase; neurodegenerative disease; in silico toxicity; molecular dynamics; multitarget ligands
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.30483

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 2.08 ± 0.16 µM) and BuChE (IC 7.41 ± 0.44 µM), corroborating the in silico results and highlighting 4a as a novel multitarget-directed AChE/BuChE inhibitor.