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

Yıl: 2023 Cilt: 30 Sayı: 2 Sayfa Aralığı: 143 - 153 Metin Dili: İngilizce DOI: 10.17343/sdutfd.1204410 İndeks Tarihi: 30-06-2023

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

Öz:
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.
Anahtar Kelime: Alzheimer’s Disease Pharmacophore Acetylcholinesterase Molecular Docking Donepezil

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

Öz:
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.
Anahtar Kelime: Alzheimer Hastalığı Farmakofor Asetilkolinesteraz Moleküler Yerleştirme Donepezil

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık
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APA Comert Onder F (2023). DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING. , 143 - 153. 10.17343/sdutfd.1204410
Chicago Comert Onder Ferah DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING. (2023): 143 - 153. 10.17343/sdutfd.1204410
MLA Comert Onder Ferah DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING. , 2023, ss.143 - 153. 10.17343/sdutfd.1204410
AMA Comert Onder F DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING. . 2023; 143 - 153. 10.17343/sdutfd.1204410
Vancouver Comert Onder F DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING. . 2023; 143 - 153. 10.17343/sdutfd.1204410
IEEE Comert Onder F "DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING." , ss.143 - 153, 2023. 10.17343/sdutfd.1204410
ISNAD Comert Onder, Ferah. "DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING". (2023), 143-153. https://doi.org/10.17343/sdutfd.1204410
APA Comert Onder F (2023). DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING. Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi, 30(2), 143 - 153. 10.17343/sdutfd.1204410
Chicago Comert Onder Ferah DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING. Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi 30, no.2 (2023): 143 - 153. 10.17343/sdutfd.1204410
MLA Comert Onder Ferah DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING. Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi, vol.30, no.2, 2023, ss.143 - 153. 10.17343/sdutfd.1204410
AMA Comert Onder F DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING. Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi. 2023; 30(2): 143 - 153. 10.17343/sdutfd.1204410
Vancouver Comert Onder F DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING. Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi. 2023; 30(2): 143 - 153. 10.17343/sdutfd.1204410
IEEE Comert Onder F "DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING." Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi, 30, ss.143 - 153, 2023. 10.17343/sdutfd.1204410
ISNAD Comert Onder, Ferah. "DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING". Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi 30/2 (2023), 143-153. https://doi.org/10.17343/sdutfd.1204410