Computational Evaluation of the Inhibitory Potential of Phytochemical Compounds on the KRAS Protein

Authors : Gülşah Aydın

Pages : 387-403

Doi:10.54370/ordubtd.1809849

View : 71 | Download : 127

Publication Date : 2025-12-27

Article Type : Research Paper

Abstract :The KRAS oncogene is a critical molecular switch governing cell proliferation, differentiation, and survival signaling, and the G12C mutation, in particular, has been identified as one of the main causes of treatment resistance in many solid tumors. In this study, the inhibitory potential of the main phytochemical compounds (α-hederin, emodin, hellebrin, kaempferol, quercetin, verbascoside, colchicine, and scopolamine) found in eight medicinal plants naturally growing in the Eastern Black Sea flora on the KRAS G12C protein was evaluated using a structure-based drug design (SBDD) approach. In this context, molecular docking simulations were performed for the Switch-II (SII-P) pocket using the high-resolution 6OIM crystal structure (KRAS G12C–GDP–sotorasib complex), and the binding energies and interaction patterns of the natural compounds were analyzed. The results revealed that α-hederin, emodin, and hellebrin exhibited stronger binding affinities than the reference inhibitor, sotorasib, and established multiple hydrogen bonds, hydrophobic interactions, and ionic interactions with critical residues such as Tyr96, His95, Gln99, Glu62–Glu63, and Cys12 in the SII-P region. The triterpenic core of α-hederin, the planar anthraquinone structure of emodin, and the glycosidic-steroidal architecture of hellebrin supported binding stability through diverse interaction strategies. These findings indicated that natural compounds found in the Eastern Black Sea flora could be considered as a potent source of pharmacophores in the development of KRAS G12C-targeted drugs.
Keywords : kanser, KRAS inhibitörleri, kenetleme simülasyonları, tıbbi bitkiler

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