Pharmacy Discipline, Life Science School, Khulna University, Khulna, 9208, Bangladesh.
Department of Pharmacy, Atish Dipankar University of Science & Technology, Dhaka, 1230, Bangladesh.
Sci Rep. 2024 Aug 27;14(1):19893. doi: 10.1038/s41598-024-70854-0.
Globally, the prevalence of breast cancer (BC) is increasing at an alarming level, despite early detection and technological improvements. Alkaloids are diverse chemical groups, and many within this class have been reported as potential anticancer compounds. Chabamide F (F) and chabamide G (G) are two dimeric amide alkaloids found in a traditional medicinal plant, Piper chaba, and possess significant cytotoxic effects. However, their scientific rationalization in BC remains unknown. Here, we aimed to investigate their potential and molecular mechanisms for BC through in silico approaches. From network pharmacology, we identified 64 BC-related genes as targets. GO and KEGG studies showed that they were involved in various biological processes and mostly expressed in BC-related pathways such as RAS, PI3K-AKT, estrogen, MAPK, and FoxO pathways. However, PPI analysis revealed SRC and AKT1 as hub genes, which play key roles in BC tumorigenesis and metastasis. Molecular docking revealed the strong binding affinity of F (- 10.7 kcal/mol) and G (- 9.4 and - 11.7 kcal/mol) for SRC and AKT1, respectively, as well as the acquisition of vital residues to inhibit them. Their long-term stability was evaluated using 200 ns molecular dynamics simulation. The RMSD, RMSF, Rg, and SASA analyses showed that the G-SRC and G-AKT1 complexes were excellently stable compared to the control, dasatinib, and capivasertib, respectively. Additionally, the PCA and DCCM analyses revealed a significant reduction in the residual correlation and motions. By contrast, the stability of the F-SRC complex was greater than that of the control, whereas it was moderately stable in complex with AKT1. The MMPBSA analysis demonstrated higher binding energies for both compounds than the controls. In particular, the binding energy of G for SRC and AKT1 was - 120.671 ± 16.997 and - 130.437 ± 19.111 kJ/mol, respectively, which was approximately twice as high as the control molecules. Van der Waal and polar solvation energies significantly contributed to this energy. Furthermore, both of them exhibited significant interactions with the binding site residues of both proteins. In summary, this study indicates that these two molecules could be a potential ATP-competitive inhibitor of SRC and an allosteric inhibitor of AKT1.
全球范围内，乳腺癌（BC）的发病率呈惊人的上升趋势，尽管早期检测和技术进步有所改善。生物碱是多种多样的化学基团，其中许多被报道为有潜在抗癌作用的化合物。查巴酰胺 F（F）和查巴酰胺 G（G）是两种二聚酰胺生物碱，存在于传统药用植物 Piper chaba 中，具有显著的细胞毒性作用。然而，它们在 BC 中的科学合理化作用尚不清楚。在这里，我们通过计算方法旨在研究它们在 BC 中的潜在和分子机制。通过网络药理学，我们确定了 64 个与 BC 相关的基因作为靶点。GO 和 KEGG 研究表明，它们参与了各种生物学过程，主要表达在与 BC 相关的途径中，如 RAS、PI3K-AKT、雌激素、MAPK 和 FoxO 途径。然而，PPI 分析显示 SRC 和 AKT1 是关键基因，它们在 BC 肿瘤发生和转移中起着关键作用。分子对接显示 F（-10.7 kcal/mol）和 G（-9.4 和-11.7 kcal/mol）对 SRC 和 AKT1 具有很强的结合亲和力，同时获得了抑制它们的重要残基。通过 200 ns 分子动力学模拟评估它们的长期稳定性。RMSD、RMSF、Rg 和 SASA 分析表明，与对照物、达沙替尼和卡匹西林相比，G-SRC 和 G-AKT1 复合物具有优异的稳定性。此外，PCA 和 DCCM 分析显示残余相关性和运动显著降低。相比之下，F-SRC 复合物的稳定性大于对照物，而与 AKT1 复合物的稳定性适中。MMPBSA 分析表明，这两种化合物的结合能都高于对照物。特别是，G 对 SRC 和 AKT1 的结合能分别为-120.671±16.997 和-130.437±19.111 kJ/mol，约为对照分子的两倍。范德华和极性溶剂化能对这种能量有显著贡献。此外，它们都与两种蛋白质的结合位点残基有显著的相互作用。综上所述，本研究表明，这两种分子可能是 SRC 的潜在 ATP 竞争性抑制剂和 AKT1 的别构抑制剂。
