Affiliation:
1. ÇANAKKALE ONSEKİZ MART ÜNİVERSİTESİ, TIP FAKÜLTESİ
Abstract
Objective
Alzheimer's disease (AD) is the most common cause
of dementia in older people due to abnormalities in
the cholinergic system. Acetylcholinesterase has
an important role in the regulation of the cholinergic
system. Therefore, targeting AChE is one of the most
promising strategies for the treatment of AD. Although
several approved drugs to treat AD, it is still needed
to develop potential inhibitor candidates. Therefore,
the aim of this study is to discover newly donepezillike
natural compounds and their synthetic derivatives
targeting acetylcholinesterase enzyme (AChE).
Material and Method
A pharmacophore model of a known drug, donepezil
was generated. Using the pharmacophore mapping
module of the Discovery Studio 2021 program,
the chemical library containing natural products
and synthetic derivatives was screened. The
pharmacokinetics and drug-likeness properties of the
screened compounds were predicted by ADMET and
Lipinski and Veber’s rule. Some criteria were used as a
filter. In addition, bioactive compounds of the database
were screened. Then, molecular docking study was
performed by using Glide/SP of Maestro (Schrödinger,
Inc.) to determine the potential molecules.
Results
The binding energies were determined for hit
compounds after molecular modeling studies.
Furthermore, H-bonding, pi-pi stacking, pi-cation,
and pi-alkyl interactions between the protein-ligand
complex have been identified by various amino acid
residues such as Tyr, Asp, His, Trp, Arg. The results
show that the potential compounds are a promising
candidate with binding energy compared to donepezil.
The molecular modeling results indicate that new
scaffolds may contribute to the discovery of new AChE
inhibitors compared to a reference drug.
Conclusion
This study may lead to further studies and contribute to
examination with in vitro analysis. The scaffolds can be
used to design novel and effective inhibitors.
Publisher
Medical Journal of Suleyman Demirel University
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