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.