Pharmaceuticals (Basel) 2025 Jun 16;186:. doi: 10.3390/ph18060902.

Exploring Brazilian Green Propolis Phytochemicals in the Search for Potential Inhibitors of B-Raf600E Enzyme: A Theoretical Approach.

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Background/Objectives: Melanoma is one of the most aggressive forms of skin cancer and is frequently associated with the B-Raf600E mutation, which constitutively activates the MAPK signaling pathway. Although selective inhibitors such as Vemurafenib offer clinical benefits, their long-term efficacy is often hindered by resistance mechanisms and adverse effects. In this study, twelve phytochemicals from Brazilian green propolis were evaluated for their potential as selective B-Raf600E inhibitors using a computational approach. Methods: Physicochemical, ADME, and electronic properties were assessed, followed by molecular docking using the B-Raf600E crystal structure (PDB ID: 3OG7). Redocking validation and 500 ns molecular dynamics simulations were performed to investigate the stability of the ligand-protein complexes, and free energy calculations were then computed. Results: Among the tested compounds, Artepillin C exhibited the strongest binding affinity (-8.17 kcal/mol) in docking and maintained stable interactions with key catalytic residues throughout the simulation, also presenting free energy of binding ΔG of -20.77 kcal/mol. HOMO-LUMO and electrostatic potential analyses further supported its reactivity and selectivity. Notably, Artepillin C remained bound within the ATP-binding site, mimicking several critical interactions observed with Vemurafenib. Results: Among the tested compounds, Artepillin C exhibited the strongest binding affinity (-8.17 kcal/mol) and maintained stable interactions with key catalytic residues throughout the simulation. HOMO-LUMO and electrostatic potential analyses further supported its reactivity and selectivity. Notably, Artepillin C remained bound within the ATP-binding site, mimicking several critical interactions observed with Vemurafenib. Conclusions: These findings indicate that Artepillin C is a promising natural compound for further development as a selective B-Raf600E inhibitor and suggest its potential utility in melanoma treatment strategies. This study reinforces the value of natural products as scaffolds for targeted drug design and supports continued experimental validation.

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