Geniş Ölçekteki Bitki ve Hayvan Kökenli Doğal İkincil Metabolitlerin FOXM1 ile Etkileşiminin Hesaplamalı Olarak Araştırılması

Yıl 2025, Cilt: 4 Sayı: 3, 63 - 72, 30.09.2025

Zekeriya Düzgün , Funda Demırtaş Korkmaz , Ebru Alp

https://doi.org/10.59518/farabimedj.1745493

Öz

FOXM1, Forkhead box ailesinden bir transkripsiyon faktörü olup, çeşitli insan malignitelerde kanserin ilerlemesi, uzak bölgelere yayılması ve kemoterapiye karşı direnç gelişmesinde rol oynayan kritik bir proto-onkogendir. Seçici ve terapötik olarak etkili FOXM1 inhibitörlerinin geliştirilmesi bu alanda önemli bir zorluk olmaya devam etmektedir. Bu çalışma, FOXM1’in DNA-bağlama alanını (DBD) hedefleyen yeni küçük molekül bileşiklerini belirlemek için çok aşamalı bir hesaplamalı yaklaşım kullanmıştır. FOXM1’in DNA-bağlama alanının kristalografik yapısına (PDB ID: 3G73) karşı geniş bir kimyasal bileşik veritabanı kullanılarak yapı-güdümlü sanal tarama işlemi gerçekleştirilmiştir. En yüksek sıralamaya sahip bileşikler, öncelikle 10-nanosaniye değerlendirmelerinden geçirilmiş, ardından kapsamlı 100-nanosaniye moleküler dinamik (MD) simülasyonları ile takip edilmiştir. Termodinamik olarak en kararlı protein-ligand komplekslerinin bağlanma afiniteleri MM/GBSA hesaplamaları ile belirlemiştir. Ön hesaplamalı tarama, -9.1 kcal/mol'den daha iyi docking skorları gösteren 21 bileşik ortaya çıkarmıştır. 10 ns MD simülasyonları sonrasında beş bileşik seçilmiş ve 100 ns MD simülasyonları bu iki bileşiğin (comp_105546, comp_112458) kararlı bağlanmasını doğrulamıştır. MM/GBSA hesaplamaları comp_112458’i en güçlü bağlayıcı (-36.25±3.5 kcal/mol) olarak belirlemiştir. Bu çalışma, FOXM1’e karşı yüksek öngörülen afinite ve kararlı bağlanma modları olan yeni kimyasal iskeletleri başarıyla tanımlamış ve hedefli antikanser ajanlarının geliştirilmesi için güçlü bir temel sağlamıştır. Bu umut verici hesaplamalı sonuçların in vitro ve in vivo çalışmalarla doğrulanması gerekmektedir.

Anahtar Kelimeler

FOXM1 , Kanser tedavisi , MM/GBSA , Moleküler dinamik , Sanal tarama

Proje Numarası

SAĞ-BAP-A-250221-45

Computational Investigation of the Interaction of Large-scale Plant and Animal-Derived Natural Secondary Metabolites with FOXM1

Öz

FOXM1, a transcription factor from the Forkhead box family, serves as a crucial proto-oncogene that plays a role in cancer advancement, spread to distant sites, and resistance to chemotherapy across various human malignancies. The development of selective and therapeutically efficient FOXM1 inhibitors remains a significant challenge in the field. This study employed a multi-step computational approach to identify novel small-molecule compounds that target the DNA-binding domain (DBD) of FOXM1. A structure-guided virtual screening process was conducted using an extensive chemical compound database, evaluated against the crystallographic structure of FOXM1’s DNA-binding domain (PDB ID: 3G73). The top-ranking compounds underwent preliminary 10-nanosecond evaluations, subsequently followed by comprehensive 100-nanosecond molecular dynamics (MD) simulations. The binding affinities of the most thermodynamically stable protein-ligand complexes were determined through MM/GBSA calculations. The preliminary computational screening revealed 21 compounds that exhibited docking scores superior to -9.1 kcal/mol. Following 10 ns MD simulations, five compounds were selected, and 100 ns MD simulations confirmed the stable binding of these two compounds (comp_105546, comp_112458). MM/GBSA calculations identified comp_112458 as the most potent binder (-36.25±3.5 kcal/mol). This study successfully identified novel chemical scaffolds with high predicted affinity and stable binding modes against FOXM1, providing a strong foundation for the development of targeted anticancer agents. These promising computational results require validation through in vitro and in vivo studies.

Anahtar Kelimeler

Cancer therapy , FOXM1 , MM/GBSA , Molecular dynamics , Virtual screening

Etik Beyan

This study does not require ethical approval as it is a computational study.

Destekleyen Kurum

This research was supported by Giresun University Scientific Research Projects Commission (Project No: SAĞ-BAP-A-250221-45).

Proje Numarası

SAĞ-BAP-A-250221-45

Teşekkür

All numerical calculations in this research were performed at TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources).

Kaynakça

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