慢性炎症导致肺癌患者患上许多疾病。肿瘤坏死因子α（TNF-α）作为一种多向性促炎性细胞因子，通过调控核因子κB（NF-κB）的活化，驱动炎症和癌症凋亡中的许多生理和病理信号通路。本研究通过虚拟对接ZINC天然产物库和计算模型分析，发现了抑制TNF-α诱导NF-κB激活的一种新的天然产物。分子动力学模拟显示，化合物SBS-3.1是与p50蛋白高效且稳定地结合的最佳领先化合物，靶向该蛋白上与DNA结合有关的重要氨基酸残基。MMP BSA (Binding Site Analysis)预测结果显示，该领先化合物与蛋白的结合自由能是有利的。该化合物能抑制TNF-α诱导的A-549细胞的增殖，其GI50值为30.53 μM。SBS-3.1能降低TNF-α诱导的NF-κB-65、p38和ERK1/2阳性肺癌细胞百分比，同时提高这些细胞的凋亡。总之，一种名为SBS-3.1的天然产物被鉴定为靶向p50的可靠化合物。SBS-3.1通过抑制NF-κB和炎症信号促进肺癌细胞的凋亡。进一步研究可以为治疗与肺癌细胞相关的炎症带来新的治疗策略。由Ramaswamy H. Sarma作通信。

Chronic inflammation leads to many maladies in lung cancer. Tumor necrosis factor-alpha (T NF- α), a pleiotropic proinflammatory cytokine regulates the activation of the nuclear factor-κB (NF-κB) to drive many physiological and pathological signaling pathways in inflammation and cancer apoptosis. This study identified a novel natural product to inhibit T NF-α induced NF-κB activation. Virtual docking of ZINC natural product library and computational modeling analysis showed compounds that target crucial amino acid residues on p50 protein involved in DNA binding. Molecular dynamic simulation showed, compound SBS-3.1, as the best lead compound that binds efficiently and stably with p50 protein. MMP BSA analysis of the lead compound predicted a favorable binding free energy. The compound inhibited the proliferations of T NF-α induced A-549 with a GI50 value of 30.53 μM. SBS-3.1 decreased the percentage of T NF-α induced NF-κB-65, p38 and ERK1/2 positive lung cancer cells, while the apoptosis in these cells were elevated. In summary, SBS-3.1, a natural product, was identified as the lead compound targeting Rel-homology region of p50. Inhibition of NF-κB and inflammatory signals by SBS 3.1 promoted apoptosis in lung cancer. Further research can bring new therapeutic strategies for treating inflammation associated T ME of lung cancer cells.Communicated by Ramaswamy H. Sarma.