A Prominent Candidate in Natural Product Discovery for Multi-Target Cancer Therapy: Structure-Based Assessment of Hyperforin

Öz

In this study, the binding affinities of nine key phytochemical compounds found in the flora of Turkey on the targets Kirsten rat sarcoma viral oncogene homolog (KRAS), Mouse double minute 2 homolog (MDM2), WEE1 G2 checkpoint kinase (WEE1), fibroblast growth factor receptor 4 (FGFR4), and Poly(ADP-ribose) polymerase 1 (PARP1) were comparatively investigated using a structure-based approach. This aimed to uncover natural molecular scaffolds that could simultaneously affect critical axes of tumor progression such as cell proliferation, DNA damage response, and mitotic control. GA-based docking studies were performed on the target structures obtained from the PDB using AutoDock. Binding modes were selected using RMSD clustering, and interaction profiles were examined in detail in 2D and 3D. The results showed that hyperforin stood out by exhibiting the strongest multiple binding performance on the targets KRAS (–8.04 kcal/mol), MDM2 (–9.15 kcal/mol), and WEE1 (–8.29 kcal/mol). Significant affinity for FGFR4 was observed only for hyperforin. Docking results for PARP1 revealed that the investigated compounds did not significantly overlap with the catalytic site. Acetylchiconine, tiliroside, and berberine were considered rational seed cells for derivative development because they offered moderate-to-high binding potential on KRAS and WEE1. Overall, the consistent and strong binding profile of hyperforin along the KRAS–MDM2–WEE1 axis suggests a multilayered suppression strategy that allows simultaneous targeting of three key oncobiological mechanisms: suppression of proliferative signaling, reactivation of the p53-mediated DNA damage response, and control of the G2/M transition. This suggests that the molecule may be a high-potential candidate for preclinical validation.

Anahtar Kelimeler

• KRAS
• MDM2
• WEE1
• Cancer
• Hyperforin

Çok Hedefli Kanser Tedavisi için Doğal Ürün Keşfinde Öne Çıkan Bir Aday: Hiperforinin Yapıya Dayalı Değerlendirmesi

Öz

Bu çalışmada, Türkiye florasında yaygın bulunan dokuz temel fitokimyasal bileşiğin KRAS (Kirsten rat sarcoma viral oncogene homolog), MDM2 (Mouse double minute 2 homolog), WEE1 (WEE1 G2 checkpoint kinase), FGFR4 (fibroblast growth factor receptor 4) ve PARP1 (Poly(ADP-ribose) polymerase 1) hedefleri üzerindeki bağlanma eğilimleri yapı-temelli yaklaşımla karşılaştırmalı olarak incelendi. Böylece hücre proliferasyonu, DNA hasar yanıtı ve mitotik kontrol gibi tümör progresyonunun kritik eksenlerini aynı anda etkileyebilecek doğal moleküler iskeletlerin ortaya çıkarılması amaçlandı. PDB’den elde edilen hedef yapılar üzerinde AutoDock ile GA-tabanlı yerleştirme çalışmaları gerçekleştirildi ve bağlanma modları RMSD-kümeleme ile seçilerek etkileşim profilleri 2-boyutlu ve 3-boyutlu olarak ayrıntılı incelendi. Elde edilen sonuçlar hiperforinin; KRAS (–8.04 kcal/mol), MDM2 (–9.15 kcal/mol) ve WEE1 (–8.29 kcal/mol) hedeflerinde en güçlü çoklu bağlanma performansını sergileyerek açık ara öne çıktığını gösterdi. FGFR4 için anlamlı afinite yalnızca hiperforinde gözlendi. PARP1 için elde edilen yerleştirme sonuçları, incelenen bileşiklerin katalitik bölgeyle anlamlı bir şekilde örtüşmediğini ortaya koydu. Asetilşikonin, tilirosid ve berberin; KRAS ve WEE1 üzerinde orta-yüksek düzeyde bağlanma potansiyeli sunduğu için türev geliştirme açısından rasyonel çekirdekler olarak değerlendirildi. Genel olarak, hiperforinin KRAS–MDM2–WEE1 ekseni boyunca tutarlı ve güçlü bağlanma profili, proliferatif sinyallemenin baskılanması, p53 aracılı DNA hasar yanıtının yeniden etkinleştirilmesi ve G2/M geçişinin kontrol altına alınması gibi üç temel onkobiyolojik mekanizmanın eşzamanlı olarak hedeflenmesine olanak tanıyan çok katmanlı bir baskılama stratejisine işaret etmekte olup, molekülün klinik öncesi doğrulamalar için yüksek potansiyele sahip bir aday olabileceğini gösterdi.

Anahtar Kelimeler

• KRAS
• MDM2
• WEE1
• Kanser
• Hiperforin

Kaynakça

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