Department of Bio-Resources, School of Biological Sciences, University of Kashmir, Srinagar, JK, India.
Department of Biology, College of Science, Hafr Al Batin University of Hafr Al-Batin, KSA.
J Biomol Struct Dyn. 2024;42(23):13002-13022. doi: 10.1080/07391102.2023.2274966. Epub 2023 Nov 10.
D. Don is a well-known medicinal plant of Kashmir Himalaya. Traditionally, it has been used to treat several diseases, including cancer. However, the molecular mechanism behind anticancer activity remains unclear. Therefore, in the present study, we have performed high performance-liquid chromatography-mass spectrometry (HR-LC/MS), network pharmacology, molecular docking and molecular dynamic (MD) simulation methods were used to explore the underlying molecular mechanism of for the treatment of breast cancer (BC). The targets of for treating BC were predicted using databases like SwissTargetPrediction, Gene Cards and OMIM. Protein-protein interaction analysis and network construction were performed using the Search Tool for the Retrieval of Interacting Genes/Proteins programme, and analysis of Gene Ontology term enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment was done using the Cytoscape programme. In addition, molecular docking was used to investigate intermolecular interactions between the compounds and the proteins using the Autodock tool. MD simulations studies were also used to explore the stability of the representative AKT1 gene peiminine and Imperialine-3-β-glucoside. In addition, experimental treatment of was also verified. HR-LC/MS detected the presence of several secondary metabolites. Afterward, molecular docking was used to verify the effective activity of the active ingredients against the prospective targets. Additionally, Peiminine and Imperialine-3-β-glucoside showed the highest binding energy score against AKT-1 (-12.99 kcal/mol and -12.08 kcal/mol). AKT1 with Peiminine and Imperialine-3-β-glucoside was further explored for MD simulations. During the MD simulation study at 100 nanoseconds, a stable complex formation of AKT1 + Peiminine and Imperialine-3-β-glucoside was observed. The binding free energy calculations using MM/GBSA showed significant binding of the ligand with protein (Δ: -79.83 ± 3.0 kcal/mol) between AKT1 + Peiminine was observed. The principal component analysis exhibited a stable converged structure by achieving global motion. Lastly, extracts also exhibited momentous anticancer activity through studies. Therefore, present study revealed the molecular mechanism of constituents for the effective treatment of BC by deactivating various multiple gene targets, multiple pathways particularly the PI3K-Akt signaling pathway. These findings emphasized the momentous anti-BC activity of constituents.Communicated by Ramaswamy H. Sarma.
唐棣是克什米尔喜马拉雅山的一种著名药用植物。传统上，它被用于治疗包括癌症在内的多种疾病。然而，其抗癌活性的分子机制尚不清楚。因此，在本研究中，我们采用高效液相色谱-质谱联用（HR-LC/MS）、网络药理学、分子对接和分子动力学（MD）模拟方法，探讨了用于治疗乳腺癌（BC）的唐棣的潜在分子机制。使用 SwissTargetPrediction、Gene Cards 和 OMIM 等数据库预测唐棣治疗 BC 的靶点。使用 Search Tool for the Retrieval of Interacting Genes/Proteins 程序进行蛋白质-蛋白质相互作用分析和网络构建，使用 Cytoscape 程序进行基因本体论术语富集和京都基因与基因组百科全书途径富集分析。此外，使用 Autodock 工具进行分子对接，研究化合物与蛋白质之间的分子相互作用。还进行了 MD 模拟研究，以探索代表性 AKT1 基因 peiminine 和 Imperialine-3-β-葡萄糖苷的稳定性。此外，还验证了唐棣的实验治疗。HR-LC/MS 检测到几种次生代谢产物的存在。随后，分子对接用于验证有效成分对预期靶点的活性。此外，Peiminine 和 Imperialine-3-β-葡萄糖苷对 AKT-1 的结合能得分最高（-12.99 kcal/mol 和-12.08 kcal/mol）。进一步对 AKT1 与 Peiminine 和 Imperialine-3-β-葡萄糖苷进行 MD 模拟研究。在 MD 模拟研究 100 纳秒时，观察到 AKT1+Peiminine 和 Imperialine-3-β-葡萄糖苷形成稳定的复合物。使用 MM/GBSA 进行的结合自由能计算表明，在 AKT1+Peiminine 之间，配体与蛋白质的结合非常紧密（Δ：-79.83±3.0 kcal/mol）。主成分分析通过实现全局运动显示了稳定收敛的结构。最后，通过 研究还发现唐棣提取物具有显著的抗癌活性。因此，本研究揭示了唐棣成分有效治疗 BC 的分子机制，通过使多种基因靶点、多条途径（特别是 PI3K-Akt 信号通路）失活。这些发现强调了唐棣成分的重要抗 BC 活性。
