title: In silico design and search for acetylcholinesterase inhibitors in Alzheimer's disease with a suitable pharmacokinetic profile and low toxicity.
abstract: 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.
authors.affiliation: Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Monte Alegre, 14040-903, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Vinicius Barreto
authors.initials: VB
authors.lastname: da Silva
authors.forename: Peterson
authors.initials: P
authors.lastname: de Andrade
authors.forename: Daniel Fábio
authors.initials: DF
authors.lastname: Kawano
authors.forename: Pedro Alves Bezerra
authors.initials: PA
authors.lastname: Morais
authors.forename: Jonathan Resende
authors.initials: JR
authors.lastname: de Almeida
authors.forename: Ivone
authors.initials: I
authors.lastname: Carvalho
authors.forename: Carlton Anthony
authors.initials: CA
authors.lastname: Taft
authors.forename: Carlos Henrique Tomich de Paula
authors.initials: CH
authors.lastname: da Silva
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular
chemical_list: D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase