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

Ferah Cömert Önder

doi:10.17343/sdutfd.1204410

Araştırma Makalesi

BibTex

RIS

Kaynak Göster

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, 143 - 153, 22.06.2023

Ferah Cömert Önder

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

Cited By: 1

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 Kelimeler

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

Kaynakça

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2. Hirbod K, Jalili-Baleh L, Nadri H, Ebrahimi SES, Moradi A, Pakseresht B, Foroumadi A, Shafiee A, Khoobi M. Coumarin derivatives bearing benzoheterocycle moiety: synthesis, cholinesterase inhibitory, and docking simulation study. Iran J Basic Med Sci. 2017;20(6):631-638. doi: 10.22038/IJBMS. 2017.8830.
3. Khoobi M, Alipour M, Sakhteman A, Nadri H, Moradi A, Ghandi M, Emami S, Foroumadi A, Shafiee A. Design, synthesis, biological evaluation and docking study of 5-oxo-4,5-dihydropyrano[ 3,2-c]chromene derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors. Eur J Med Chem. 2013;68:260-9. doi: 10.1016/j.ejmech.2013.07.038.
4. Gupta S, Fallarero A, Järvinen P, Karlsson D, Johnson MS, Vuorela PM, Mohan CG. Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques. Bioorg Med Chem Lett. 2011;21(4):1105-12. doi: 10.1016/j.bmcl.2010.12.131.
5. Arumugam N, Almansour AI, Kumar RS, Kotresha D, Saiswaroop R, Venketesh S. Dispiropyrrolidinyl-piperidone embedded indeno[1,2-b]quinoxaline heterocyclic hybrids: Synthesis, cholinesterase inhibitory activity and their molecular docking simulation. Bioorg Med Chem. 2019;27(12):2621-2628. doi: 10.1016/j.bmc.2019.03.058.
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7. Tehrani MB, Rezaei Z, Asadi M, Behnammanesh H, Nadri H, Afsharirad F, Moradi A, Larijani B, Mohammadi-Khanaposhtani M, Mahdavi M. Design, Synthesis, and Cholinesterase Inhibition Assay of Coumarin-3-carboxamide-N-morpholine Hybrids as New Anti-Alzheimer Agents. Chem Biodivers. 2016;16(7):e1900144. doi: 10.1002/cbdv.201900144.
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9. Sharma K. Cholinesterase inhibitors as Alzheimer's therapeutics (Review). Mol Med Rep. 2019;20(2):1479-1487. doi: 10.3892/mmr.2019.10374.
10. Howes MJ, Perry NS, Houghton PJ. Plants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disorders. Phytother Res. 2003;17(1):1-18. doi: 10.1002/ptr.1280.
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FARMAKOFOR HARİTALAMA-ESASLI SANAL TARAMA VE MOLEKÜLER YERLEŞTİRME İLE BELİRLENEN POTANSİYEL ASETİLKOLİNESTERAZ İNHİBİTÖRLERİ OLARAK DONEPEZİL-BENZERİ BİLEŞİKLERİN KEŞFİ

Yıl 2023, Cilt: 30 Sayı: 2, 143 - 153, 22.06.2023

Ferah Cömert Önder

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

Cited By: 1

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 Kelimeler

Alzheimer Hastalığı, Farmakofor, Asetilkolinesteraz, Moleküler Yerleştirme, Donepezil

Kaynakça

1. Huang W, Tang L, Shi Y, Huang S, Xu L, Sheng R, Wu P, Li J, Zhou N, Hu Y. Searching for the Multi-Target-Directed Ligands against Alzheimer's disease: discovery of quinoxaline-based hybrid compounds with AChE, H₃R and BACE 1 inhibitory activities. Bioorg Med Chem. 2011;19(23):7158-67. doi: 10.1016/j. bmc.2011.09.061.
2. Hirbod K, Jalili-Baleh L, Nadri H, Ebrahimi SES, Moradi A, Pakseresht B, Foroumadi A, Shafiee A, Khoobi M. Coumarin derivatives bearing benzoheterocycle moiety: synthesis, cholinesterase inhibitory, and docking simulation study. Iran J Basic Med Sci. 2017;20(6):631-638. doi: 10.22038/IJBMS. 2017.8830.
3. Khoobi M, Alipour M, Sakhteman A, Nadri H, Moradi A, Ghandi M, Emami S, Foroumadi A, Shafiee A. Design, synthesis, biological evaluation and docking study of 5-oxo-4,5-dihydropyrano[ 3,2-c]chromene derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors. Eur J Med Chem. 2013;68:260-9. doi: 10.1016/j.ejmech.2013.07.038.
4. Gupta S, Fallarero A, Järvinen P, Karlsson D, Johnson MS, Vuorela PM, Mohan CG. Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques. Bioorg Med Chem Lett. 2011;21(4):1105-12. doi: 10.1016/j.bmcl.2010.12.131.
5. Arumugam N, Almansour AI, Kumar RS, Kotresha D, Saiswaroop R, Venketesh S. Dispiropyrrolidinyl-piperidone embedded indeno[1,2-b]quinoxaline heterocyclic hybrids: Synthesis, cholinesterase inhibitory activity and their molecular docking simulation. Bioorg Med Chem. 2019;27(12):2621-2628. doi: 10.1016/j.bmc.2019.03.058.
6. Montanari S, Scalvini L, Bartolini M, Belluti F, Gobbi S, Andrisano V, Ligresti A, Di Marzo V, Rivara S, Mor M, Bisi A, Rampa A. Fatty Acid Amide Hydrolase (FAAH), Acetylcholinesterase (AChE), and Butyrylcholinesterase (BuChE): Networked Targets for the Development of Carbamates as Potential Anti-Alzheimer's Disease Agents. J Med Chem. 2016;59(13):6387-406. doi: 10.1021/acs.jmedchem.6b00609.
7. Tehrani MB, Rezaei Z, Asadi M, Behnammanesh H, Nadri H, Afsharirad F, Moradi A, Larijani B, Mohammadi-Khanaposhtani M, Mahdavi M. Design, Synthesis, and Cholinesterase Inhibition Assay of Coumarin-3-carboxamide-N-morpholine Hybrids as New Anti-Alzheimer Agents. Chem Biodivers. 2016;16(7):e1900144. doi: 10.1002/cbdv.201900144.
8. Ferreira-Vieira TH, Guimaraes IM, Silva FR, Ribeiro FM. Alzheimer's disease: Targeting the Cholinergic System. Curr Neuropharmacol. 2016;14(1):101-15. doi: 10.2174/1570159x13666150716165726.
9. Sharma K. Cholinesterase inhibitors as Alzheimer's therapeutics (Review). Mol Med Rep. 2019;20(2):1479-1487. doi: 10.3892/mmr.2019.10374.
10. Howes MJ, Perry NS, Houghton PJ. Plants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disorders. Phytother Res. 2003;17(1):1-18. doi: 10.1002/ptr.1280.
11. Comert Onder F, Sahin K, Senturk M, Durdagi S, Ay M. Identifying highly effective coumarin-based novel cholinesterase inhibitors by in silico and in vitro studies. J Mol Graph Model. 2022;115:108210. doi: 10.1016/j.jmgm.2022.108210.
12. Li P, Niu Y, Li S, Zu X, Xiao M, Yin L, Feng J, He J, Shen Y. Identification of an AXL kinase inhibitor in triple-negative breast cancer by structure-based virtual screening and bioactivity test. Chem Biol Drug Des. 2022;99(2):222-232. doi: 10.1111/ cbdd.13977.
13. Lu SH, Wu JW, Liu HL, Zhao JH, Liu KT, Chuang CK, Lin HY, Tsai WB, Ho Y. The discovery of potential acetylcholinesterase inhibitors: a combination of pharmacophore modeling, virtual screening, and molecular docking studies. J Biomed Sci. 2011;18(1):8. doi: 10.1186/1423-0127-18-8.
14. Qing X, Lee XY, De Raeymaecker J, Tame J, Zhang K, De Maeyer M, Voet A. Pharmacophore modeling: advances, limitations, and current utility in drug discovery. J Receptor, Ligand and Channel Res. 2014;7:81–92. doi:10.2147/JRLCR.S46843.
15. Kaserer T, Beck KR, Akram M, Odermatt A, Schuster D. Pharmacophore Models and Pharmacophore-Based Virtual Screening: Concepts and Applications Exemplified on Hydroxysteroid Dehydrogenases. Molecules. 2015;20(12):22799-832. doi:10.3390/molecules201219880.
16. Lakra N, Matore BW, Banjare P, Singh R, Singh J, Roy PP. Pharmacophore based virtual screening of cholinesterase inhibitors: search of new potential drug candidates as antialzheimer agents. In Silico Pharmacol. 2022 Sep 29;10(1):18. doi: 10.1007/s40203-022-00133-1.
17. Jang C, Yadav DK, Subedi L, Venkatesan R, Venkanna A, Afzal S, Lee E, Yoo J, Ji E, Kim SY, Kim MH. Identification of novel acetylcholinesterase inhibitors designed by pharmacop- hore-based virtual screening, molecular docking and bioassay. Sci Rep. 2018;8(1):14921. doi: 10.1038/s41598-018-33354-6.
18. Korabecny J, Dolezal R, Cabelova P, Horova A, Hruba E, Ricny J, Sedlacek L, Nepovimova E, Spilovska K, Andrs M, Musilek K, Opletalova V, Sepsova V, Ripova D, Kuca K. 7-MEOTA-donepezil like compounds as cholinesterase inhibitors: Synthesis, pharmacological evaluation, molecular modeling and QSAR studies. Eur J Med Chem. 2014;82:426-38. doi: 10.1016/j.ejmech. 2014.05.066.
19. Brunetti L, Leuci R, Carrieri A, Catto M, Occhineri S, Vinci G, Gambacorta L, Baltrukevich H, Chaves S, Laghezza A, Altomare CD, Tortorella P, Santos MA, Loiodice F, Piemontese L. Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease. Eur J Med Chem. 2022;237:114358. doi: 10.1016/j.ejmech. 2022.114358.
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Toplam 49 adet kaynakça vardır.

Ayrıntılar

Birincil Dil	İngilizce
Konular	Klinik Tıp Bilimleri
Bölüm	Araştırma Makaleleri
Yazarlar	Ferah Cömert Önder 0000-0002-4037-1979
Yayımlanma Tarihi	22 Haziran 2023
Gönderilme Tarihi	15 Kasım 2022
Kabul Tarihi	14 Mart 2023
Yayımlandığı Sayı	Yıl 2023 Cilt: 30 Sayı: 2

Kaynak Göster

Vancouver	Cömert Önder F. DISCOVERY OF DONEPEZIL-LIKE COMPOUNDS AS POTENTIAL ACETYLCHOLINESTERASE INHIBITORS DETERMINED BY PHARMACOPHORE MAPPING-BASED VIRTUAL SCREENING AND MOLECULAR DOCKING. SDÜ Tıp Fak Derg. 2023;30(2):143-5.

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https://doi.org/10.1080/07391102.2023.2291830

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