AbstractBreast Cancer (BC) is the most common cause of cancer-associated deaths in females worldwide. Despite advancements in BC treatment driven by extensive characterization of its molecular hallmarks, challenges such as drug resistance, tumor relapse, and metastasis persist. Therefore, there is an urgent need for alternative treatment approaches with multi-modal efficacy to overcome these hurdles.

。尽管BC治疗因其分子标志的广泛表征而取得了进展，但耐药性，肿瘤复发和转移等挑战仍然存在。因此，迫切需要具有多模式功效的替代治疗方法来克服这些障碍。

In this context, natural bioactives are increasingly recognized for their pivotal role as anti-cancer compounds. This study focuses on predicting molecular targets for key herbal phytoconstituents—gallic acid, piperine, quercetin, resveratrol, and beta-sitosterol—present in the polyherbal formulation, Krishnadi Churna.

在这种情况下，天然生物活性物质因其作为抗癌化合物的关键作用而越来越受到认可。这项研究的重点是预测多草药配方Krishnadi搅拌剂中存在的关键草药植物成分没食子酸，胡椒碱，槲皮素，白藜芦醇和β-谷甾醇的分子靶标。

Using an in-silico network pharmacology model, key genes were identified and docked against these marker compounds and controls. Mammary carcinoma emerged as the most significant phenotype of the putative targets. Analysis of an online database revealed that out of 135 predicted targets, 134 were mutated in breast cancer patients.

使用计算机网络药理学模型，鉴定关键基因并与这些标记化合物和对照对接。乳腺癌成为推定靶标中最重要的表型。对在线数据库的分析表明，在135个预测目标中，有134个在乳腺癌患者中发生了突变。

Notably, ESR1, CYP19A1, and EGFR were identified as key genes which are known to regulate the BC progression. Docking studies demonstrated that the herbal phytoconstituents had similar or better docking scores than positive controls for these key genes, with convincing protein-ligand interactions confirmed by molecular dynamics simulations, MM/GBSA and free energy landscape (FEL) analysis.

值得注意的是，ESR1，CYP19A1和EGFR被确定为已知调节BC进展的关键基因。对接研究表明，草药植物成分对这些关键基因的对接得分与阳性对照相似或更好，通过分子动力学模拟，MM/GBSA和自由能景观（FEL）分析证实了令人信服的蛋白质-配体相互作用。

Overall, this study highlights the predictive potential of herbal phytoconstituents in targeting BC genes, suggesting their promise as a basis for developing new therapeutic formulations for BC..

总的来说，这项研究突出了草药植物成分在靶向BC基因方面的预测潜力，表明它们有望成为开发BC新治疗制剂的基础。。

IntroductionBreast cancer (BC) is the most prominent malignancy among females worldwide and as per GLOBOCAN 2022 reports, it accounts for 23.8% of the total cancer cases and shares the highest cancer mortality rate (15.4% of the total cancer deaths)1. BC is a heterogeneous disease at the molecular level, and is clinically categorized as luminal estrogen receptor-positive (ER+) and progesterone receptor positive (PR+); human epidermal growth factor receptor 2 positive (HER2+); and triple-negative breast cancer (TNBC)2.

引言乳腺癌（BC）是全球女性中最突出的恶性肿瘤，根据GLOBOCAN 2022报告，它占总癌症病例的23.8%，癌症死亡率最高（占总癌症死亡率的15.4%）1。；人表皮生长因子受体2阳性（HER2+）；和三阴性乳腺癌（TNBC）2。

Locoregional therapies (surgery and radiotherapy) are major modalities for BC management, but de-escalation schemes have become the standard of care today. Over the decade, the treatment options have been chosen by considering the molecular heterogeneity of breast cancer, and importance is given to biologically directed therapies or targeted therapies, especially in HER2 + and TNBC3.

局部治疗（手术和放疗）是BC管理的主要方式，但降级方案已成为当今的护理标准。在过去的十年中，通过考虑乳腺癌的分子异质性来选择治疗方案，并且重视生物定向疗法或靶向疗法，特别是在HER2++和TNBC3中。

Several systemic therapies including endocrine therapy, chemotherapy, immunotherapy, etc. have been adapted as part of the treatment regime4.Despite significant improvement in current therapy and appreciable progress in scientific research for targeting breast cancer and extending a patient’s life; there exists a gap in the complete prevention or cure of the disease either because the treatment response is often short-term, or mostly prone to resistance like endocrine resistance or chemotherapy resistance, or due to high metastasis of breast cancer cells4,5.

包括内分泌治疗，化疗，免疫治疗等在内的几种全身治疗已被调整为治疗方案的一部分4。尽管目前的治疗方法有了显着改善，针对乳腺癌和延长患者寿命的科学研究取得了明显进展；完全预防或治疗该疾病存在差距，因为治疗反应通常是短期的，或者大多容易产生内分泌耐药或化疗耐药等耐药，或者由于乳腺癌细胞的高转移4,5。

Hence, there is an urgent need to explore molecular causal factors and an appropriate treatment regime, which can overcome the hurdles of existing therapy.In this context, natural bioactive compounds from Indian Traditional Medicine (Ayurveda) have shown positive outcomes in preventing cancer or suppressing its progression.

因此，迫切需要探索分子因果因素和适当的治疗方案，这可以克服现有治疗的障碍。在这种情况下，来自印度传统医学（阿育吠陀）的天然生物活性化合物在预防癌症或抑制其进展方面显示出积极的结果。

Data availability

数据可用性

All the data generated have been submitted with this manuscript.

生成的所有数据均已与本手稿一起提交。

AbbreviationsBC:

缩写BC：

Breast cancer

乳腺癌

TNBC:

TNBC：

Triple-negative breast cancer

三阴性乳腺癌

ER:

Estrogen-receptor

雌激素受体

PR:

公共关系：

Progesterone-receptor

孕酮受体

HER 2:

她的2：

Human epidermal growth factor receptor

人表皮生长因子受体

CYP19A1:

CYP19A1:

Cytochrome p450 family 19 subfamily a member 1

EGFR:

EGFR：

Epidermal growth factor receptor

表皮生长因子受体

MAPK:

MAPK公司：

Mitogen-activated protein kinases

丝裂原活化蛋白激酶

MDR:

Multi-drug resistance

多重耐药性

RMSD:

RMSD：

Root mean square deviation

均方根偏差

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Download referencesAcknowledgementsAuthors thank All India Institute of Ayurveda, New Delhi, India for providing infrastructural and library support. Authors acknowledge Dr Vinod Devaraji, Schrodinger India for his support for structural analysis studies.Author informationAuthor notesHeena Saini and Prashant Kumar Gupta contributed equally to this work.Authors and AffiliationsIntegrated Translational Molecular Biology Unit (ITMBU), Department of Rog Nidan Evam Vikriti Vigyan (Pathology), All India Institute of Ayurveda, New Delhi, 110076, IndiaHeena Saini & Richa TripathiAyurinformatics Laboratory, Department of Kaumarabhritya (Pediatrics), All India Institute of Ayurveda, New Delhi, 110076, IndiaPrashant Kumar Gupta, Arun Kumar Mahapatra & Shrikrishna RajagopalaDepartment of DravyaGuna (Materia Medica & Pharmacology), All India Institute of Ayurveda, New Delhi, 110076, IndiaTanuja NesariAuthorsHeena SainiView author publicationsYou can also search for this author in.

下载参考文献致谢作者感谢印度新德里阿育吠陀全印度研究所提供的基础设施和图书馆支持。作者感谢Schrodinger India的Vinod Devaraji博士对结构分析研究的支持。作者信息作者notesHeena Saini和Prashant Kumar Gupta对这项工作做出了同样的贡献。作者和附属机构综合翻译分子生物学单位（ITMBU），Rog Nidan Evam Vikriti Vigyan（病理学），全印度阿育吠陀研究所，新德里，110076，IndiaHeena Saini＆Richa TripathiAyurinformatics Laboratory，Kaumarabhritya（儿科），全印度阿育吠陀研究所，新德里，110076，IndiaPrashant Kumar Gupta，Arun Kumar Mahapatra＆Shrikrishna Rajagopala DravyaGuna系《本草医学与药理学》），全印度阿育吠陀研究所，新德里，110076，IndiaTanuja NesariAuthorsHeena SainiView作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarPrashant Kumar GuptaView author publicationsYou can also search for this author in

PubMed Google ScholarPrashant Kumar GuptaView作者出版物您也可以在

PubMed Google ScholarArun Kumar MahapatraView author publicationsYou can also search for this author in

PubMed谷歌学者Kumar MahapatraView作者出版物您也可以在

PubMed Google ScholarShrikrishna RajagopalaView author publicationsYou can also search for this author in

PubMed Google ScholarRicha TripathiView author publicationsYou can also search for this author in

PubMed Google ScholarRicha TripathiView作者出版物您也可以在

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PubMed Google ScholarContributionsConceptualization: H.S, T.N.; Methodology: H.S, P.K.G; Software: H.S, P.K.G, A.K.M; Formal analysis: H.S, P.K.G; Investigation: H.S; Writing –original draft preparation: H.S, P.K.G; Writing – review, and editing.: H.S, P.K.G, R.T; Visualisation.: H.S; Supervision.: T.N., S.K.R.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献概念：H.S，T.N。；方法：H.S，P.K.G；软件：H.S，P.K.G，A.K.M；形式分析：H.S，P.K.G；调查：H.S；写作-原稿准备：H.S，P.K.G；写作-评论和编辑：H、 S，P.K.G，R.T；可视化：H、 S；监督：T、 N.，S.K.R。通讯作者通讯。

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Reprints and permissionsAbout this articleCite this articleSaini, H., Gupta, P.K., Mahapatra, A.K. et al. Deciphering the multi-scale mechanism of herbal phytoconstituents in targeting breast cancer: a computational pharmacological perspective.

转载和许可本文引用本文Saini，H.，Gupta，P.K.，Mahapatra，A.K。等人。解读草药植物成分靶向乳腺癌的多尺度机制：计算药理学观点。

Sci Rep 14, 23795 (2024). https://doi.org/10.1038/s41598-024-75059-zDownload citationReceived: 29 June 2024Accepted: 01 October 2024Published: 11 October 2024DOI: https://doi.org/10.1038/s41598-024-75059-zShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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KeywordsBreast cancerHerbal phytoconstituents Traditional MedicineNetwork pharmacologyMolecular dockingMolecular dynamics Ayurveda

关键词乳腺癌皮肤植物成分传统医学网络药理学分子对接分子动力学阿育吠陀