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.

Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

“…The structure of AChE and BChE has been extensively reviewed in the following publications [7,29,37,38]. In brief, AChE has a more developed peripheral anionic site and narrower aromatic gorge than BChE.…”

Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer’s disease (Review)

“…No significant differences were found in the levels of the amine metabolites homovanillic acid and methoxyhydroxyphenylglycol in the CSF of drug-free patients with AD as compared with those in a group of controls, showing that AD was not associated with changes in central catecholamine metabolism and increased platelet MAO activity (70). In view of MAO being involved in the metabolic inactivation of several monoaminergic neurotransmitters, including 5-HT, melatonin, NE and EP (21,70,71), a complex dysfunction in the MAO system is likely to be present in AD (48,69). Furthermore, MAO activity may be used to distinguish patients with AD due to the existence of a biologically-based behavioral subtype of AD (72).…”

Research Strategies Developed for the Treatment of Alzheimer’s Disease. Reversible and Pseudo-Irreversible Inhibitors of Acetylcholinesterase: Structure-Activity Relationships and Drug Design

“…The toxicophoric and pharmacokinetic predictions constitute valuable tools helping the continuous search for pharmaceutical interesting molecules with low toxicity and suitable pharmacokinetic profile [26]. The toxicophoric and pharmacokinetic predictions constitute valuable tools helping the continuous search for pharmaceutical interesting molecules with low toxicity and suitable pharmacokinetic profile [26].…”

“…In addition, virtual-screening simulations have been used to select novel inhibitor candidates containing different structural scaffolds in order to find novel structural patterns with potential AChE inhibitory activity [26]. Several N-alkyl-phenyl substituents appear as favorable since the PAS is predominantly composed of hydrophobic aromatic residues.…”