Fenazin Türevi Bileşikler İçin Moleküler Docking Çalışması: Kolinesterazlar ve Alzheimer Hastalığı

Yıl 2025, Cilt: 6 Sayı: 2, 27 - 33, 07.09.2025

Seda Onder , Mehmet Özcan

Öz

Giriş: Alzheimer hastalığı (AH), günümüzde kesin tedavisi bulunmayan, ilerleyici nörodejeneratif bir bozukluktur. Kolinerjik hipoteze göre, asetilkolin (ACh) düzeylerinin azalması hastalığın bilişsel belirtilerine katkıda bulunur. Bu nedenle AChE ve BChE enzimlerinin inhibisyonu, yeni nesil ilaç tasarımlarında önemli bir stratejidir. Bu çalışmada, fenazin türevi dört boyanın (Safranin O, Phenosafranine, Pyocyanine ve Janus Green B) AChE ve BChE enzimleri üzerindeki inhibitör potansiyelleri moleküler yerleştirme (docking) yöntemiyle değerlendirilmiştir.
Materyal ve Metodlar: Ligand yapıları PubChem veri tabanından temin edilerek Avogadro yazılımı ile MMFF94 kuvvet alanı kullanılarak enerji minimizasyonu yapılmıştır. Hedef proteinler olan insan AChE (PDB: 4M0E) ve BChE (PDB: 6QAA) yapıları RCSB Protein Data Bank’tan elde edilmiş, ön işlemden geçirilerek docking analizlerine hazır hale getirilmiştir. Moleküler yerleştirme analizleri AutoDock Vina (v1.2.5) ile gerçekleştirilmiştir. Elde edilen kompleksler Discovery Studio ile analiz edilerek bağlanma enerjileri ve etkileşim tipleri değerlendirilmiştir.
Bulgular: Janus Green B, AChE için en yüksek bağlanma skorunu (–9.2 kcal/mol) göstermiştir. BChE için ise en güçlü bağlanma Safranin O (–9.1 kcal/mol) ile elde edilmiştir. Phenosafranine’nin BChE ile etkileşimi (–8.9 kcal/mol) de dikkat çekicidir. Moleküler etkileşim analizleri; AChE için TRP286, TYR341 ve TYR124 gibi aromatik kalıntıların; BChE için TRP82, PHE329 ve HIS438 gibi kalıntıların ligand bağlanmasında merkezi rol oynadığını göstermiştir. Tüm ligandlar enzimlerin aktif bölgelerinde hidrojen bağları, π-alkil ve elektrostatik etkileşimler sergilemiştir. Çalışmanın bulguları, fenazin türevli boyaların, özellikle Janus Green B ve Phenosafranine’in, AChE ve BChE enzimlerine karşı güçlü bağlanma gösterdiğini ortaya koymaktadır. Bu moleküller, Alzheimer hastalığına karşı geliştirilecek yeni inhibitör adayları arasında değerlendirilebilir. Bulgular in silico verilere dayanmakla birlikte, biyolojik geçerlilik için ileri in vitro ve in vivo çalışmalarla desteklenmelidir.

Anahtar Kelimeler

Alzheimer hastalığı , fenazin , kolinesteraz inhibisyonu , asetilkolinesteraz , bütirilkolinesteraz

Etik Beyan

BU ÇALISMA İÇİN ETIK KURULA İHTİYAC YOKTUR

Molecular Docking Study for Phenazine Derivative Compounds: Cholinesterases and Alzheimer’s disease

Öz

Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no definitive treatment to date. According to the cholinergic hypothesis, decreased acetylcholine (ACh) levels contribute to the cognitive symptoms of the disease. Therefore, inhibition of AChE and BChE enzymes is an important strategy in next-generation drug design. In this study, the inhibitory potentials of four phenazine-derived dyes (Safranin-O, Phenosafranine, Pyocyanine and Janus Green B) on AChE and BChE enzymes were evaluated by molecular docking method. Material and Methods: Ligand structures were obtained from PubChem database and energy minimization was performed using MMFF94 force field with Avogadro software. The structures of target proteins, human AChE (PDB: 4M0E) and BChE (PDB: 6QAA), were obtained from RCSB Protein Data Bank and preprocessed to make them ready for docking analyses. Molecular docking analyses were performed with AutoDock Vina (v1.2.5). The complexes obtained were analyzed with Discovery Studio to evaluate binding energies and interaction types. Results: Janus Green B showed the highest binding score for AChE (–9.2 kcal/mol). The strongest binding for BChE was obtained with Safranin-O (–9.1 kcal/mol). The interaction of Phenosafranine with BChE (–8.9 kcal/ mol) is also remarkable. Molecular interaction analyses showed that aromatic residues such as TRP286, TYR341 and TYR124 for AChE and residues such as TRP82, PHE329 and HIS438 for BChE play a central role in ligand binding. All ligands exhibited hydrogen bonds, π-alkyl and electrostatic interactions in the active sites of the enzymes. The findings of the study show that phenazine-derived dyes, especially Janus Green B and Phenosafranine, exhibit strong binding to AChE and BChE enzymes. These molecules can be evaluated among the new inhibitor candidates to be developed against Alzheimer’s disease. Although the findings are based on in silico data, they should be supported by further in vitro and in vivo studies for biological validity.

Anahtar Kelimeler

Alzheimer’s disease , phenazine , cholinesterase inhibition , acetylcholinesterase , butyrylcholinesterase

Kaynakça

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