Calendula officinalis as a source of KRAS-targeted anticancer agents: a comprehensive computational assessment

KRAS mutations are among the most potent oncogenic drivers in several highly aggressive cancers, including pancreatic, colorectal, and non-small cell lung cancer (NSCLC), and are typically associated with poor clinical outcomes and resistance to conventional therapies. Mutant KRAS proteins, particularly those with alterations at codons 12, 13, and 61, remain challenging therapeutic targets due to their constitutive activation and disruption of key signaling pathways.

A combined computational pipeline was employed to identify promising inhibitors. Selected phytochemicals from Calendula officinalis were screened for drug-likeness using Lipinski's Rule of Five and evaluated for their ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties. Docking protocol validation was performed by redocking co-crystallized ligands into their original binding sites, yielding RMSD values ≤ 2.0 Å, which confirmed the reliability of the docking approach. Binding interactions with KRAS mutants were analyzed using molecular docking via AutoDock Vina. To enhance accuracy, structural data from the Protein Data Bank (PDB) were incorporated. Promising candidates were further examined through molecular dynamics simulations and MM-GBSA analysis to estimate their binding free energies.

The computational analysis revealed several C. officinalis compounds with strong binding affinities toward key KRAS mutants, particularly G12C, G13D, and G12V. All top compounds complied with ADMET, exhibited no predicted mutagenicity or hepatotoxicity, and showed low predicted acute toxicity. These compounds demonstrated favorable drug-likeness and ADMET profiles, supporting their potential as viable lead structures.

Despite the historical challenges in targeting KRAS-mutant proteins, the findings of this study support the potential of natural products as scaffolds for anticancer drug discovery as a source for developing novel anticancer therapies. The identified phytochemicals from C. officinalis such as calendasaponin D and procyanidin A2 may serve as potential leads for future preclinical and experimental validation against KRAS-driven malignancies.