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

Authors : Gülşah Aydın

Pages : 75-95

Doi:10.55385/kastamonujes.1824730

View : 84 | Download : 257

Publication Date : 2025-12-25

Article Type : Research Paper

Abstract :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.
Keywords : KRAS, MDM2, WEE1, Kanser, Hiperforin

ORIGINAL ARTICLE URL