Department of Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Mangalore, Karnataka, 575018, India.
Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Mangalore, Karnataka, 575018, India.
Sci Rep. 2024 Sep 14;14(1):21486. doi: 10.1038/s41598-024-72475-z.
Naringin, a flavonoid, exhibits diverse therapeutic properties and has been proven to exert cytotoxic effects on cancer cells. Nevertheless, the precise mechanism of naringin maintaining its cytotoxic effect on glioblastoma (GBM) remains unknown. Thus, the current study aimed to establish a plausible cellular mechanism for Naringin's inhibition of GBM. We employed various system biology techniques to forecast the primary targets, including gene ontology and cluster analysis, KEGG enrichment pathway estimation, molecular docking, MD (molecular dynamic) simulation and MMPBSA analysis. Glioblastoma target sequences were obtained via DisGeNet and Therapeutic Target Prediction, aligned with naringin targets, and analyzed for gene enrichment and ontology. Gene enrichment analysis identified the top ten hub genes. Further, molecular docking was conducted on all identified targets. For molecular dynamics modelling, we selected the two complexes that exhibited the most docking affinity and the two most prominent genes of the hub identified through analysis of the enrichment of genes. The PARP1 and ALB1 signalling pathways were found to be the main regulated routes. Naringin exhibited the highest binding potential of - 12.90 kcal/mol with PARP1 (4ZZZ), followed by ABL1 (2ABL), with naringin showing a - 8.4 kcal/mol binding score, as determined by molecular docking. The molecular dynamic approach and MM-PBSA investigation along with PCA study revealed that the complex of Naringin, with 4ZZZ (PARP1) and, 2ABL (ABL1), are highly stable compared to that of imatinib and talazoparib. Analyses of the signalling pathway suggested that naringin may have anticancer effects against GBM by influencing the protein PARP and ALB1 levels. Cytotoxicity assay was performed on two different glioblastoma cell lines C6 and U87MG cells. Naringin demonstrates a higher cytotoxic potency against U87MG human glioblastoma cells compared to C6 rat glioma cells.
柚皮苷是一种类黄酮，具有多种治疗特性，已被证明对癌细胞具有细胞毒性作用。然而，柚皮苷维持对神经胶质瘤（GBM）的细胞毒性作用的确切机制尚不清楚。因此，本研究旨在建立柚皮苷抑制 GBM 的合理细胞机制。我们采用了各种系统生物学技术来预测主要靶点，包括基因本体论和聚类分析、KEGG 富集途径估计、分子对接、MD（分子动力学）模拟和 MMPBSA 分析。通过 DisGeNet 和治疗靶点预测获得神经胶质瘤靶点序列，与柚皮苷靶点对齐，并进行基因富集和本体分析。基因富集分析确定了前 10 个枢纽基因。进一步对所有鉴定的靶点进行分子对接。对于分子动力学建模，我们选择了两个表现出最强结合亲和力的复合物，以及通过基因富集分析鉴定的两个最突出的枢纽基因。PARP1 和 ALB1 信号通路被发现是主要调节途径。柚皮苷与 PARP1（4ZZZ）的结合能最高，为-12.90 kcal/mol，其次是 ABL1（2ABL），结合能为-8.4 kcal/mol，这是通过分子对接确定的。分子动力学方法和 MM-PBSA 研究以及 PCA 研究表明，与伊马替尼和他拉唑帕尼相比，柚皮苷与 4ZZZ（PARP1）和 2ABL（ABL1）的复合物更稳定。信号通路分析表明，柚皮苷可能通过影响蛋白 PARP 和 ALB1 水平对 GBM 发挥抗癌作用。在两种不同的神经胶质瘤细胞系 C6 和 U87MG 细胞上进行了细胞毒性测定。柚皮苷对 U87MG 人神经胶质瘤细胞的细胞毒性比 C6 大鼠神经胶质瘤细胞更强。
