Molecular perception of interactions between bis(7)tacrine and cystamine-tacrine dimer with cholinesterases as the promising proposed agents for the treatment of Alzheimer’s disease

Abstract

The infamous chronic neurodegenerative disease, Alzheimer's, that starts with short-term memory loss and eventually leads to gradual bodily function decline which has been attributed to the deficiency in brain neurotransmitters, acetylcholine, and butylcholine. As a matter of fact, design of compounds that can inhibit cholinesterases activities (acetylcholinesterase and butylcholinesterase) has been introduced as an efficient method to treat Alzheimer's. Among proposed compounds, bis(7)tacrine (B7T) is recognized as a noteworthy suppressor for Alzheimer's disease. Recently a new analog of B7T, cystamine-tacrine dimer is offered as an agent to detain Alzheimer's complications, even better than the parent compound. In this study, classical molecular dynamic simulations have been employed to take a closer look into the modes of interactions between the mentioned ligands and both cholinesterase enzymes. According to our obtained results, the structural differences in the target enzymes active sites result in different modes of interactions and inhibition potencies of the ligands against both enzymes. The obtained information can help to investigate those favorable fragments in the studied ligands skeletons that have raised the potency of the analog in comparison with the parent compound to design more potent multi target ligands to heal Alzheimer's disease.

Therapeutic Potential of Multifunctional Tacrine Analogues

“…Different interactions of both target cholinesterases with the target ligands have been demonstrated and the roles of the important residues in the active sites have been investigated. Integration of bis(7)tacrine and cystamine (as an antioxidant) has introduced cystamine-tacrine dimer with a very good inhibition performance that simultaneously affects several pathogens of Alzheimer’s disease [137].…”

Computational evidence to design an appropriate candidate for the treatment of Alzheimer's disease through replacement of the heptamethylene linker of bis(7)tacrine with S-allylcysteine

“…[46][47][48][49][50] Moreover, much evidence acknowledge the role of this compound in preventing the progression of AD with several mechanisms: antioxidant, antiamyloidogenic, anti-inammatory, antitangle, and antiglycative activities. 58 The obtained results in our previous study for the protonation states of AChE and BChE residues and the obtained settings for computational methods have been used in the current study. In this regard, bis(7)tacrine is an excellent candidate that ll the distance of 14Å between the CAS and PAS sites perfectly and its tetrahydroanthracene fragments engage the active site aromatic residues in the target enzymes.…”

“…We obtained a very good agreement between our theoretical results and experimental data. 58 The obtained results in our previous study for the protonation states of AChE and BChE residues and the obtained settings for computational methods have been used in the current study.…”