de Souza Garcia Ferreira, Santana Airis Farias, Antunes Fernanda Sanches Kuhl, Cogo Ramon Martins, Pereira Matheus Dornellas, Rando Daniela Gonçales Galasse, Gonçalves Carolina Passarelli
Biological Science Department, Instituto Universitario Italiano de Rosario, Corrientes 720, PB y 1er Piso Rosario S2000CTT, Santa Fe, Argentina.
Cosmobeauty, Avenida Aruanã 1160, Barueri 06460-010, SP, Brazil.
Pharmaceuticals (Basel). 2025 Jun 16;18(6):902. doi: 10.3390/ph18060902.
Melanoma is one of the most aggressive forms of skin cancer and is frequently associated with the B-RafE 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-RafE inhibitors using a computational approach. Physicochemical, ADME, and electronic properties were assessed, followed by molecular docking using the B-RafE 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. 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. These findings indicate that Artepillin C is a promising natural compound for further development as a selective B-RafE 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.
黑色素瘤是最具侵袭性的皮肤癌形式之一，常与B-RafE突变相关，该突变可组成性激活丝裂原活化蛋白激酶（MAPK）信号通路。尽管像维莫非尼这样的选择性抑制剂具有临床益处，但其长期疗效常因耐药机制和不良反应而受阻。在本研究中，使用计算方法评估了巴西绿蜂胶中的12种植物化学物质作为选择性B-RafE抑制剂的潜力。评估了其物理化学性质、药物代谢动力学（ADME）性质和电子性质，随后使用B-RafE晶体结构（PDB ID：3OG7）进行分子对接。进行了重新对接验证和500纳秒的分子动力学模拟以研究配体-蛋白质复合物的稳定性，然后计算自由能。结果：在测试的化合物中，阿替匹林C在对接中表现出最强的结合亲和力（-8.17千卡/摩尔），并且在整个模拟过程中与关键催化残基保持稳定的相互作用，其结合自由能ΔG为-20.77千卡/摩尔。最高占据分子轨道（HOMO）-最低未占据分子轨道（LUMO）和静电势分析进一步支持了其反应性和选择性。值得注意的是，阿替匹林C保留在ATP结合位点内，模拟了与维莫非尼观察到的几种关键相互作用。在测试的化合物中，阿替匹林C表现出最强的结合亲和力（-8.17千卡/摩尔），并且在整个模拟过程中与关键催化残基保持稳定的相互作用。HOMO-LUMO和静电势分析进一步支持了其反应性和选择性。值得注意的是，阿替匹林C保留在ATP结合位点内，模拟了与维莫非尼观察到的几种关键相互作用。这些发现表明，阿替匹林C是一种有前景的天然化合物，可进一步开发为选择性B-RafE抑制剂，并表明其在黑色素瘤治疗策略中的潜在效用。本研究强化了天然产物作为靶向药物设计支架的价值，并支持持续的实验验证。
