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

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.