这项工作通过研究柚皮苷和芦丁与关键 DDR 蛋白（包括 PARP-1、ATM、ATR、CHK1 和 WEE1）的相互作用来检查它们影响 DNA 损伤反应 (DDR) 途径的能力。通过结合计算机分子对接和体外评估，我们研究了这些化合物对 MDA-MB-231 细胞的细胞毒性和基因毒性作用，并将其与正常人成纤维细胞 (2DD) 和静止成纤维细胞 (QFC) 进行比较。研究发现柚皮苷和芦丁对DDR通路蛋白具有很强的亲和力，表明它们具有特异性调节癌细胞中DDR通路的能力。两种化合物都对癌细胞表现出优先的细胞毒性，同时保留正常 2DD 成纤维细胞的活力，如 10 µM 剂量下进行的细胞毒性实验所证明的那样。特别是在 QFC 细胞上进行的彗星实验提供了有关柚皮苷和芦丁的基因毒性影响的宝贵信息，强调了癌细胞中 DNA 损伤的靶向启动。这种差异强调需要使用精确的细胞模型来适当评估毒性和遗传毒性。此外，ADMET 和药物相似性研究强调了这些化合物的药理学潜力；然而，他们也指出有必要进行优化以改善其治疗效果。使用浓度为 10 µM 的 DPPH 和自由基清除测定法评估柚皮苷和芦丁的抗氧化能力。结果证实，这两种化合物都具有减少氧化应激的作用，从而增强其抗癌作用。总体而言，柚皮苷和芦丁显示出作为在癌症治疗中调节 DDR 的药物的潜力。它们对癌细胞表现出选择性毒性，同时不伤害正常细胞，并具有很强的抗氧化特性。该分析增强了我们对天然化学物质在癌症治疗中的治疗用途的理解，支持对其作用机制和临床有效性进行更多研究的需要。© 2024。作者。

This work examines the capacity of Naringin and Rutin to influence the DNA damage response (DDR) pathway by investigating their interactions with key DDR proteins, including PARP-1, ATM, ATR, CHK1, and WEE1. Through a combination of in silico molecular docking and in vitro evaluations, we investigated the cytotoxic and genotoxic effects of these compounds on MDA-MB-231 cells, comparing them to normal human fibroblast cells (2DD) and quiescent fibroblast cells (QFC). The research found that Naringin and Rutin had strong affinities for DDR pathway proteins, indicating their capacity to specifically regulate DDR pathways in cancer cells. Both compounds exhibited preferential cytotoxicity towards cancer cells while preserving the vitality of normal 2DD fibroblast cells, as demonstrated by cytotoxicity experiments conducted at a dose of 10 µM. The comet experiments performed particularly on QFC cells provide valuable information on the genotoxic impact of Naringin and Rutin, highlighting the targeted initiation of DNA damage in cancer cells. The need to use precise cell models to appropriately evaluate toxicity and genotoxicity is emphasized by this discrepancy. In addition, ADMET and drug-likeness investigations have emphasized the pharmacological potential of these compounds; however, they have also pointed out the necessity for optimization to improve their therapeutic profiles. The antioxidant capabilities of Naringin and Rutin were assessed using DPPH and free radical scavenging assays at a concentration of 10 µM. The results confirmed that both compounds have a role in reducing oxidative stress, hence enhancing their anticancer effects. Overall, Naringin and Rutin show potential as medicines for modulating the DDR in cancer treatment. They exhibit selective toxicity towards cancer cells while sparing normal cells and possess strong antioxidant properties. This analysis enhances our understanding of the therapeutic uses of natural chemicals in cancer treatment, supporting the need for more research on their mechanisms of action and clinical effectiveness.© 2024. The Author(s).