DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING

ÖNDER F. C.

Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi, cilt.30, sa.2, ss.143-153, 2023 (Hakemli Dergi) identifier

Özet

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.