网络药理学与对从阿久哇枣（L.）中提取的植物化学物质的阐释，以抑制导致三阴性乳腺癌（TNBC）的Akt和PI3K

Network Pharmacology and Elucidation of Phytochemicals Extracted from Ajwa Dates ( L.) to Inhibit Akt and PI3K Causing Triple Negative Breast Cancer (TNBC).

作者信息

Bashar Md Abul, Hossain Md Arju, Kavey Md Reduanul Haque, Shazib Rayhanuzzaman, Islam Md Shofiqul, Ansari Siddique Akber, Rahman Md Habibur

机构信息

Department of Pharmacy, Faculty of Biological Sciences, Islamic University, Kushtia 7003, Bangladesh.

Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh.

出版信息

Curr Pharm Des. 2025;31(10):774-796. doi: 10.2174/0113816128348876241017101729.

DOI:10.2174/0113816128348876241017101729

PMID:39698883

Abstract

BACKGROUND

About 10-15% of all breast cancers comprise triple-negative breast cancer (TNBC), defined as cancer cells that lack ER, PR, and HER2 protein receptors. Due to the absence of these receptors, treating TNBC using conventional chemotherapy is challenging and, therefore, requires the discovery of novel chemotherapeutic agents derived from natural sources.

OBJECTIVE

The current work was intended to study the potential phytochemicals of Ajwa dates ( L.) with the predicted potential targets (namely, Akt and PI3K) to determine possible TNBC inhibitors.

METHODS

We harnessed network pharmacology, molecular docking, drug-likeness studies, Molecular Dynamics (MD) simulation, and binding free energy (MM-GBSA) calculation to get phytochemicals with potential effects against TNBC. Firstly, molecular docking was performed on 125 phytochemicals against the Akt and PI3K proteins utilizing PyRx. Then, the phytochemicals with the highest binding affinity (≤ -8.1 kcal/mol) were examined for drug-likeness and toxicity profiles. Finally, phytochemicals with optimal druglikeness and toxicity profiles were studied by Molecular Dynamics (MD) simulation and binding free energy (MM-GBSA) to identify compounds that can form stable complexes.

RESULTS

The results of the network pharmacology revealed that the Akt and PI3K proteins are potential targets of TNBC for the phytochemicals of L. used in this study. The outcomes of molecular docking displayed that among 125 phytochemicals, 42 of them (with a binding affinity ≤ -8.1 kcal/mol) have potentially inhibiting effects on both proteins PI3K and Akt expressed in TNBC. Then, the results of drug-likeness identified seven phytochemicals with optimal pharmacokinetic profiles. Furthermore, toxicity studies showed that three phytochemicals (namely, Chrysoeriol, Daidzein, and Glycitein) did not cause any toxicities. Finally, the Molecular Dynamics (MD) simulation studies and binding free energy (MM-GBSA) verified that Daidzein stayed within the binding cavities of both proteins (Akt and PI3K) by establishing a stable protein-ligand complex during simulation.

CONCLUSION

Taken together, the current work emphasizes the potential effects of Daidzein from L. against TNBC, and it can be further studied to establish it as a standard chemotherapy for TNBC.

摘要

背景

所有乳腺癌中约10 - 15%为三阴性乳腺癌（TNBC），即癌细胞缺乏雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体2（HER2）蛋白受体。由于缺乏这些受体，使用传统化疗治疗TNBC具有挑战性，因此需要发现源自天然来源的新型化疗药物。

目的

当前研究旨在研究阿久哇枣（学名： Phoenix dactylifera L.）的潜在植物化学物质及其预测的潜在靶点（即Akt和PI3K），以确定可能的TNBC抑制剂。

方法

我们利用网络药理学、分子对接、类药性研究、分子动力学（MD）模拟和结合自由能（MM - GBSA）计算来获取对TNBC有潜在作用的植物化学物质。首先，使用PyRx对125种植物化学物质针对Akt和PI3K蛋白进行分子对接。然后，检查结合亲和力最高（≤ - 8.1千卡/摩尔）的植物化学物质的类药性和毒性概况。最后，通过分子动力学（MD）模拟和结合自由能（MM - GBSA）研究具有最佳类药性和毒性概况的植物化学物质，以鉴定能够形成稳定复合物的化合物。

结果

网络药理学结果表明，Akt和PI3K蛋白是本研究中所使用的枣（学名： Phoenix dactylifera L.）植物化学物质的TNBC潜在靶点。分子对接结果显示，在125种植物化学物质中，其中42种（结合亲和力≤ - 8.1千卡/摩尔）对TNBC中表达的PI3K和Akt两种蛋白均有潜在抑制作用。然后，类药性结果鉴定出7种具有最佳药代动力学特征的植物化学物质。此外，毒性研究表明，三种植物化学物质（即 Chrysoeriol、大豆苷元和黄豆黄素）未引起任何毒性。最后，分子动力学（MD）模拟研究和结合自由能（MM - GBSA）验证了大豆苷元在模拟过程中通过建立稳定的蛋白质 - 配体复合物而停留在两种蛋白（Akt和PI3K）的结合腔内。