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

Year 2023, , 143 - 153, 22.06.2023

Ferah Cömert Önder

https://doi.org/10.17343/sdutfd.1204410

Cited By: 1

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.

Keywords

Donepezil, Alzheimer’s Disease, Pharmacophore, Acetylcholinesterase, Molecular Docking

FARMAKOFOR HARİTALAMA-ESASLI SANAL TARAMA VE MOLEKÜLER YERLEŞTİRME İLE BELİRLENEN POTANSİYEL ASETİLKOLİNESTERAZ İNHİBİTÖRLERİ OLARAK DONEPEZİL-BENZERİ BİLEŞİKLERİN KEŞFİ

Abstract

Amaç
Alzheimer hastalığı yaşlı insanlarda kolinerjik sistemdeki
anormalliklerden dolayı bunamanın en yaygın
nedenidir. Asetilkolinesteraz kolinerjik sistemin düzenlenmesinde
önemli bir role sahiptir. Bu nedenle, AChE'yi
hedeflemek AH tedavisi için en umut verici stratejilerden
biridir. AH tedavisi için onaylanmış birkaç
ilaç olmasına rağmen potansiyel inhibitör adaylarının
keşfedilmesine halen ihtiyaç vardır. Bu nedenle, bu
çalışmanın amacı asetilkolinesteraz enzimini (AChE)
hedef alan yeni donepezil benzeri doğal bileşiklerin ve
bunların sentetik türevlerinin keşfedilmesidir.
Gereç ve Yöntem
Bilinen bir ilaç olan donepezilin farmakofor modeli
oluşturulmuştur. Discovery Studio 2021 programının
farmakofor haritalama modülü kullanılarak doğal ürün
ve sentetik türevlerini içeren kimyasal kütüphanesi taranmıştır.
Taranan bileşiklerin farmakokinetik ve ilaca
benzer özellikleri ADMET ve Lipinski ve Veber kuralı
ile tahmin edilmiştir. Filtre olarak bazı kriterler kullanılmıştır.
Ayrıca veri tabanının biyoaktif bileşikleri taranmıştır.
Daha sonra, potansiyel molekülleri belirlemek
için Maestro Glide/SP (Schrödinger, Inc.) kullanılarak
moleküler yerleştirme çalışması yapılmıştır.
Bulgular
Moleküler modelleme çalışmalarının ardından öncü
bileşikler için bağlanma enerjileri belirlendi. Ayrıca,
protein-ligand kompleksi arasındaki H-bağ, pi-pi istifleme,
pi-katyon ve pi-alkil etkileşimleri, Tyr, Asp, His,
Trp, Arg gibi çeşitli amino asit kalıntıları ile tanımlanmıştır.
Sonuçlar, potansiyel bileşiklerin donepezil ile
karşılaştırıldığında bağlanma enerjisi ile umut verici
bir aday olduğunu göstermektedir. Moleküler modelleme
sonuçları, yeni yapı iskelelerinin standart ilaca
kıyasla yeni AChE inhibitörlerinin keşfedilmesine katkıda
bulunabileceğini belirtmektedir.
Sonuç
Bu çalışma daha ileri çalışmalara yol açabilir ve in
vitro analizlerle incelenmesine katkı sağlayabilir. Yapı
iskeleleri, yeni ve etkili inhibitörlerin tasarlanması için
kullanılabilir.

Keywords

Alzheimer Hastalığı, Farmakofor, Asetilkolinesteraz, Moleküler Yerleştirme, Donepezil

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