In silico design and search for acetylcholinesterase inhibitors in Alzheimer's disease with a suitable pharmacokinetic profile and low toxicity

Alzheimer's disease is a complex neurodegenerative disorder of the central nervous system, characterized by amyloid-β deposits, τ-protein aggregation, oxidative stress and reduced levels of acetylcholine in the brain. One pharmacological approach is to restore acetylcholine level by inhibiting...

Full description

Saved in:

Bibliographic Details
Published in:	Future medicinal chemistry Vol. 3; no. 8; p. 947
Main Authors:	da Silva, Vinicius Barreto, de Andrade, Peterson, Kawano, Daniel Fábio, Morais, Pedro Alves Bezerra, de Almeida, Jonathan Resende, Carvalho, Ivone, Taft, Carlton Anthony, da Silva, Carlos Henrique Tomich de Paula
Format:	Journal Article
Language:	English
Published:	England 01-06-2011
Subjects:	Acetylcholinesterase - metabolism Alzheimer Disease - drug therapy Alzheimer Disease - enzymology Animals Cholinesterase Inhibitors - chemistry Cholinesterase Inhibitors - pharmacokinetics Cholinesterase Inhibitors - pharmacology Cholinesterase Inhibitors - toxicity Drug Design Humans Models, Molecular
Online Access:	Get more information
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Alzheimer's disease is a complex neurodegenerative disorder of the central nervous system, characterized by amyloid-β deposits, τ-protein aggregation, oxidative stress and reduced levels of acetylcholine in the brain. One pharmacological approach is to restore acetylcholine level by inhibiting acetylcholinesterase (AChE) with reversible inhibitors, such as galanthamine, thus helping to improve the cognitive symptoms of the disease. In order to design new galanthamine derivatives and search for novel, potential inhibitors with improved interactions, as well as a suitable pharmacokinetic profile and low toxicity, several molecular modeling techniques were applied. These techniques included the investigation of AChE-drug complexes (1QT1 and 1ACJ Protein Data Bank codes), ligand-binding sites calculation within the active site of the enzyme, pharmacophore perception of galanthamine derivatives, virtual screening, toxicophorical analysis and estimation of pharmacokinetics properties. A total of four galanthamine derivatives having a N-alkyl-phenyl chain were designed, since the tertiary amine substituents could reach the peripheral anionic site that is not occupied by galanthamine. In addition, 12 drug-like compounds from the Ilibdiverse database were selected by virtual screening as novel, hypothetical AChE inhibitors. The toxicophorical analysis revealed that only four proposed inhibitors have chemical groups able to develop mutagenicity and chromosome damage. The remaining compounds showed only mild or none toxicophorical alerts. At least three screened compounds presented theoric parameters consistent with good oral bioavailability. The designed molecules have the potential to become new lead compounds that might guide the design of drugs with optimized pharmacodynamic and pharmacokinetic properties in order to improve the treatment of Alzheimer's disease by creating new pharmacotherapeutic options.
ISSN:	1756-8927
DOI:	10.4155/FMC.11.67