Sankaranarayanan Pranaya, G Dicky John Davis, Pa Abhinand, Manikandan M, Ghosh Arabinda
Department of Bioinformatics, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, Tamil Nadu, 600116, India.
Department of Medical Genetics, Manipal Hospitals, Bengaluru, Karnataka, 560 017, India.
F1000Res. 2025 Mar 18;13:1271. doi: 10.12688/f1000research.155657.2. eCollection 2024.
Triple-negative breast cancers (TNBC) are defined as tumors that lack the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It exhibits unique clinical and pathological features, demonstrates high aggressiveness, and has a relatively poor prognosis and clinical outcome.
To identify a novel drug target protein against TNBC and potential phytochemical lead molecules against the identified target.
In this study, we retrieved TNBC samples from NGS and microarray datasets in the Gene Expression Omnibus database. We employed a combination of differential gene expression studies, protein-protein interaction analysis, and network topology investigation to identify the target protein. Additionally, the molecular docking and molecular dynamics (MD) simulation studies followed by Molecular Mechanics with Generalised Born Surface Area salvation was used to identify potential lead molecule.
The upregulated genes with LogFC > 1.25 and P-value < 0.05 from the TNBC gene expression dataset were identified. Androgen receptor (AR) was found to be an appropriate hub target in the protein-protein interaction network. Phytochemicals that inhibit breast cancer target were retrieved from the PubChem database and virtual screening was performed using PyRx against the AR protein. Thereby, the AR was found to be the target protein and 2-hydroxynaringenin was discovered to be a possible phytochemical lead molecule for combating TNBC. Moreover, the AR and the 2-hydroxynaringenin complex showed structural stability and higher binding affinity through molecular dynamics and MM-GBSA studies.
AR was identified as a hub protein that is highly expressed in breast cancer and 2-hydroxynaringenin efficacy of counter TNBC requires further investigation both in vitro and in vivo.
三阴性乳腺癌（TNBC）被定义为缺乏雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体2（HER2）表达的肿瘤。它具有独特的临床和病理特征，表现出高侵袭性，预后和临床结局相对较差。
确定一种针对TNBC的新型药物靶点蛋白以及针对所确定靶点的潜在植物化学先导分子。
在本研究中，我们从基因表达综合数据库的NGS和微阵列数据集中检索TNBC样本。我们采用差异基因表达研究、蛋白质-蛋白质相互作用分析和网络拓扑研究相结合的方法来确定靶点蛋白。此外，通过分子对接和分子动力学（MD）模拟研究，随后采用广义玻恩表面积溶剂化的分子力学方法来确定潜在的先导分子。
从TNBC基因表达数据集中鉴定出LogFC>1.25且P值<0.05的上调基因。雄激素受体（AR）被发现是蛋白质-蛋白质相互作用网络中合适的枢纽靶点。从PubChem数据库中检索出抑制乳腺癌靶点的植物化学物质，并使用PyRx针对AR蛋白进行虚拟筛选。由此，发现AR为靶点蛋白，2-羟基柚皮素被发现是一种对抗TNBC的可能的植物化学先导分子。此外，通过分子动力学和MM-GBSA研究，AR与2-羟基柚皮素复合物显示出结构稳定性和更高的结合亲和力。
AR被鉴定为在乳腺癌中高表达的枢纽蛋白，2-羟基柚皮素对抗TNBC的疗效需要在体外和体内进一步研究。
