Talidomid ve Analoglarının BCL-2 ve BRCA1 Üzerindeki Silico Etkileri: Moleküler Yerleştirme, Moleküler Dinamikler ve Görüntüleme Çalışmaları

Abstract

Moleküler biyolojide in silico çalışmalar, son yıllarda özellikle biyomedikal araştırmalarda deneysel süreçleri hızlandıran ve ekonomik avantaj sağlayan yöntemlerden biri olarak öne çıkmaktadır. Bilgisayar destekli bir yaklaşım olan in silico yöntemler; kanser araştırmalarında yeni hedeflerin belirlenmesi, moleküler etkileşimlerin görselleştirilerek analiz edilmesi ve kimyasal bileşiklerin ilaç adayı potansiyellerinin değerlendirilmesi gibi temel alanlarda önemli katkılar sunmaktadır. Bu çalışmanın amacı, talidomid ve analoglarının (lenalidomid, pomalidomid) kanserle ilişkili BCL-2 ve BRCA1 proteinleriyle etkileşimlerini in silico yöntemlerle analiz ederek potansiyel inhibitör adaylarını belirlemektir. Moleküler docking analizleri AutoDock Vina ile, moleküler dinamik (MD) simülasyonları ise WebGro moleküler dinamik hesaplama sitesi kullanılarak 50 ns süreyle yürütülmüştür. Sistem kararlılığı RMSD, RMSF ve Rg analizleriyle değerlendirilmiştir. Docking sonuçlarına göre, BCL-2 proteiniyle talidomid, lenalidomid ve pomalidomidin bağlanma enerjileri sırasıyla –6,8, –6,6 ve –6,7 kcal/mol’dür. BRCA1 proteiniyle talidomid -5,3, lenalidomid -6,7, pomalidomid -5,5 olarak hesaplanmıştır. MD simülasyonları hem serbest proteinlerin hem de protein-ligand komplekslerinin kompakt ve kararlı yapılarını koruduğunu göstermiştir. RMSD değerlerinin 0,3–0,5 nm aralığında sabitlenmesi, sistemlerin dinamik stabilitesini desteklemiştir. Özellikle talidomid ve lenalidomidin BCL-2 komplekslerinde yapısal stabiliteyi artırdığı belirlenmiştir. Sonuç olarak, talidomid türevlerinin BCL-2 ve BRCA1 proteinlerine orta düzeyde bağlanma afinitesi ve kompleks stabilitesi göstermesi, bu bileşiklerin anti-kanser terapötik ajan adayları olarak değerlendirilebileceğini ortaya koymaktadır. Gelecekteki in vitro ve in vivo çalışmalar bu bulguların biyolojik geçerliliğini güçlendirecektir.

Keywords

• BCL-2
• talidomid
• moleküler kenetlenme
• in silico analizler
• moleküler dinamik

In Silico Effects of Thalidomide and Its Analogs on BCL-2 and BRCA1: Molecular Docking, Molecular Dynamics and Imaging Studies

Abstract

In recent years, in silico studies in molecular biology have emerged as a leading approach that accelerates experimental processes and provides economic advantages, particularly in biomedical research. As a computer-aided strategy, in silico methods contribute significantly to key areas such as the identification of novel therapeutic targets in cancer research, the visualization and analysis of molecular interactions, and the evaluation of the drug-likeness potential of chemical compounds. This study aimed to analyze the interactions of thalidomide and its analogs (lenalidomide, pomalidomide) with cancer-related proteins BCL-2 and BRCA1 using in silico approaches, in order to identify potential inhibitor candidates. Molecular docking analyses were performed using AutoDock Vina, and molecular dynamics (MD) simulations were conducted for 50 ns on the WebGro molecular dynamics computation site. System stability was assessed by RMSD, RMSF, and Rg analyses. Docking results showed that the binding energies of thalidomide, lenalidomide and pomalidomide with the BCL-2 protein were –6.8, –6.6, and –6.7 kcal/mol, respectively. For the BRCA1 protein, the binding energies were –5.3, –5.5, and –6.7 kcal/mol, respectively. MD simulations demonstrated that both free proteins and protein–ligand complexes maintained compact and stable structures throughout the simulation. The RMSD values stabilized between 0.3 and 0.5 nm, supporting the dynamic stability of the systems. Notably, thalidomide and lenalidomide enhanced the structural stability of the BCL-2 complexes. In conclusion, thalidomide derivatives exhibit moderate binding affinity and complex stability to BCL-2 and BRCA1 proteins, suggesting that these compounds can be considered as candidates for anti-cancer therapeutic agents. Future in vitro and in vivo studies are expected to further validate the biological relevance of these findings.

Keywords

• BCL-2
• thalidomide
• molecular docking
• molecular dynamic
• in silico analysis

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