Parkinson Hastalığında Mitokondriyal Disfonksiyonu Hedefleyen İlaç Yeniden Konumlandırma: Network Analizi ve In Silico Moleküler Docking Aracılı FBXO7 Odaklı Bir Yaklaşım

Abstract

FBXO7, mitofaji, proteazomal degradasyon ve sinaptik işlevlerde rol oynayan, Parkinson hastalığı (PH)'nda umut vadeden ancak yeterince araştırılmamış bir terapötik hedeftir. Parkinson hastalığında PH’de mitokondriyal disfonksiyonu hedef alan, FBXO7 merkezli bir ilaç yeniden konumlandırma yaklaşımının terapötik potansiyelini araştırmayı amaçlamaktadır. Bu amaçla, STRING veritabanı kullanılarak bir protein-protein etkileşim (PPI) ağı oluşturulmuş; ardından FBXO7 ile ilişkili temel biyolojik yolları belirlemek için Gen Ontolojisi (GO) ve KEGG zenginleştirme analizleri gerçekleştirilmiştir. Ayrıca, seçilen klinik olarak onaylı ilaçların FBXO7’ye bağlanma afinitelerini değerlendirmek ve PH tedavisi için yeniden konumlandırılmaya uygun adayları belirlemek üzere SwissDock üzerinden AutoDock Vina algoritması kullanılarak in silico moleküler docking çalışmaları yapılmıştır. Docking analizi sonucunda FBXO7’ye yüksek bağlanma afinitesi gösteren çeşitli bileşikler tanımlanmıştır: florometolon (–6,367 kcal/mol), bendroflumetiyazid (–6,354 kcal/mol), lasofoksifen (–6,173 kcal/mol), penisilin V (–6,102 kcal/mol), hidromorfon (–6,067 kcal/mol) ve sefamandol (–6,036 kcal/mol). Bu ilaçlar, mitokondri işlevi, nöroinflamasyon ve hücresel stres yanıtlarıyla ilişkili biyolojik yollarla bağlantılı olup, PH'de hastalık modifiye edici ajanlar olma potansiyeline sahiptir. Ancak, hastalık progresyonunu kötüleştirme veya sistemik yan etkiler gibi sınırlılıklar doğrudan yeniden kullanımını kısıtlayabilir. Bu çalışma, FBXO7 ile yüksek bağlanma afinitesi gösteren klinik olarak onaylı çeşitli ilaçları ortaya koyarak, bunların PH’de mitokondriyal disfonksiyonu hedeflemek için potansiyel taşıdığını göstermektedir. Bazı bileşiklerin doğrudan kullanımıyla ilgili zorluklar bulunsa da, elde edilen moleküler etkileşim verileri mitokondri odaklı yeni tedavi stratejileri geliştirmek için değerli bilgiler sunmaktadır. Terapötik potansiyelin artırılması ve yan etkilerin azaltılması için ileri düzey deneysel doğrulama ve yapısal optimizasyon gereklidir; bu da PPH için yeni tedavi yaklaşımlarının önünü açabilir.

Keywords

• FBXO7
• ilaç yeniden konumlandırma
• mitokondriyal disfonksiyon
• nörodejenerasyon
• Parkinson hastalığı

Drug Repurposing Targeting Mitochondrial Dysfunction in Parkinson's Disease: FBXO7-Focused Approach Through Network Analysis and In Silico Molecular Docking

Abstract

FBXO7 is a promising but underexplored therapeutic target in Parkinson’s disease (PD), having role in mitophagy, proteasomal degradation, and synaptic function. This study aims to investigate the therapeutic potential of targeting mitochondrial dysfunction in PD through an FBXO7-centered drug repurposing approach. A protein-protein interaction (PPI) network was constructed using the STRING database, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify key pathways associated with FBXO7. Additionally, in silico molecular docking was conducted using the AutoDock Vina algorithm in SwissDock to evaluate the binding affinities of selected clinically approved drugs to FBXO7 and identify promising candidates for potential repurposing in PD treatment. Docking analysis identified several compounds with high binding affinity to FBXO7, including fluorometholone (-6.367 kcal/mol), bendroflumethiazide (-6.354 kcal/mol), lasofoxifene (-6.173 kcal/mol), penicillin V (-6.102 kcal/mol), hydromorphone (-6.067 kcal/mol), and cefamandole (-6.036 kcal/mol). These drugs are involved in biological pathways related to mitochondrial function, neuroinflammation, and cellular stress responses, highlighting their potential as disease-modifying agents in PD. However, limitations such as the potential for exacerbating disease progression or systemic side effects may restrict their direct repurposing. This study highlights several clinically approved drugs with high binding affinities to FBXO7, suggesting their potential for targeting mitochondrial dysfunction in PD. While some compounds may present challenges for or direct use, their molecular interactions offer valuable insights for developing novel mitochondrial-targeted therapies. Further experimental validation and structural optimization are required to enhance their therapeutic potential and minimize side effects, paving the way for novel therapeutic strategies in PD.

Keywords

• FBXO7
• drug repurposing
• mitochondrial dysfunction
• neurodegeneration
• Parkinson

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