Kolinesteraz ve Ferroptosis'in Çift İnhibitörü Olarak Keşfedilmemiş Doğal Bileşikler: Yedi Biyoaktif Fitokimyasal Üzerine Nöroprotektif Bir Bakış Açısı

Öz

Amaç: Bu çalışmada, celastrol, pachypodol, hinokitiol, withanone, isobavachalcone, magnolol ve xanthorrhizol olmak üzere yedi doğal bileşiğin AChE ve BChE’ye karşı çift hedefli bağlanma potansiyeli, donepezil ve rivastigmin referans alınarak incelendi. Gereç ve Yöntem: Moleküler yapılar PubChem veritabanından elde edilerek MMFF94 kuvvet alanı ile enerji minimizasyonu yapıldı. Moleküler kenetleme (docking) analizleri AutoDock Vina kullanılarak insan AChE (PDB ID: 4M0E) ve BChE (PDB ID: 6QAA) üzerinde gerçekleştirildi. Bağlanma afiniteleri ve etkileşim profilleri Discovery Studio Visualizer ile değerlendirildi. Bulgular: Isobavachalcone (–9.2 kcal/mol) ve magnolol (–8.4 kcal/mol) AChE için yüksek afinite gösterirken, withanone (–9.7 kcal/mol) ve celastrol (–9.6 kcal/mol) BChE’ye güçlü bağlanma potansiyeli sergilemiş ve donepezil ile karşılaştırılabilir sonuçlar vermiştir. Bu bileşikler, hidrojen bağları, π–π etkileşimleri ve hidrofobik temaslar gibi stabilizasyon sağlayan etkileşimler oluşturmuş, minimal sterik çatışma ile enzimlerin aktif bölgelerine yapısal uyumluluk göstermiştir. Sonuç: Isobavachalcone, magnolol, celastrol ve withanone, umut verici çok işlevli adaylar olarak belirlenmiştir. Çift yönlü kolinesteraz inhibisyonu ve bildirilen antioksidan özellikleri, hem kolinerjik disfonksiyon hem de ferroptozisle ilişkili nörodejenerasyonu hedefleyen yeni tedavi stratejileri için potansiyel taşımaktadır.

Anahtar Kelimeler

• Alzheimer hastalığı
• doğal bileşikler
• ferroptozis
• kolinesteraz inhibitörleri
• moleküler kenetlenme
• nörodejenerasyon

Unexplored Natural Compounds as Dual Inhibitors of Cholinesterase and Ferroptosis: A Neuroprotective Perspective on Seven Bioactive Phytochemicals

Öz

Objective: This study investigated the dual-target binding potential of seven natural compounds celastrol, pachypodol, hinokitiol, withanone, isobavachalcone, magnolol, and xanthorrhizol against AChE and BChE, using donepezil and rivastigmine as references. Material and Method: Molecular structures were obtained from PubChem and energy-minimised with the MMFF94 force field. Docking was performed using AutoDock Vina with human AChE (PDB ID: 4M0E) and BChE (PDB ID: 6QAA). Binding affinities and interaction profiles were assessed with Discovery Studio Visualizer. Results: Isobavachalcone (–9.2 kcal/mol) and magnolol (–8.4 kcal/mol) showed high affinity for AChE, while withanone (–9.7 kcal/mol) and celastrol (–9.6 kcal/mol) strongly bound BChE, comparable to donepezil. These compounds established stabilising interactions, including hydrogen bonds, π–π stacking, and hydrophobic contacts, with minimal steric conflicts, supporting structural compatibility with target enzymes. Conclusion:Isobavachalcone, magnolol, celastrol, and withanone are identified as promising multifunctional candidates. Their dual cholinesterase inhibition and reported antioxidant properties suggest potential to address both cholinergic dysfunction and ferroptosis-associated neurodegeneration, warranting further experimental validation.

Anahtar Kelimeler

• Alzheimer’s disease
• Natural compounds
• Ferroptosis
• Cholinesterase inhibitors
• Molecular docking
• Neurodegeneration

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