{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T11:02:36Z","timestamp":1784804556725,"version":"3.55.0"},"reference-count":96,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Breast cancer (BC) remains a leading cause of cancer-related mortality in women worldwide.\n                    <jats:italic>Scutellaria barbata<\/jats:italic>\n                    , a traditional Chinese medicinal herb, possesses recognized anticancer properties, but its mechanistic role in BC is not fully elucidated. This study employed an integrated\n                    <jats:italic>in silico<\/jats:italic>\n                    approach to identify the key flavonoids, targets, and pathways through which\n                    <jats:italic>S. barbata<\/jats:italic>\n                    exerts its anti-BC effects. A multi-step computational methodology incorporating network pharmacology, molecular docking, and dynamics simulations was utilized to profile bioactive compounds from\n                    <jats:italic>S. barbata<\/jats:italic>\n                    . From an initial set of 34 phytocompounds, three flavonoids namely apigenin, 4\u2019-hydroxywogonin, and hispidulin demonstrated favorable drug-likeness, high bioavailability, and low predicted acute oral toxicity (LD\u2085\u2080\u2009&gt;\u2009500 mg\/kg) profiles. Network analysis identified AKT1, IL6 and TNF as central hub targets, significantly enriched in the PI3K-Akt, MAPK, and TNF signaling pathways. Molecular docking showed strong binding affinities (\u2264 \u20137.5 kcal\/mol) between these flavonoids and the hub proteins, with hispidulin (\u20138.1 kcal\/mol) and apigenin (\u20137.7 kcal\/mol) exhibiting the highest affinity for AKT1 than other hub proteins. Molecular dynamics simulations over 100 ns further revealed that the apigenin-AKT1 complexes exhibited greater stability with lower RMSD fluctuations, reduced residue flexibility (RMSF), stable radius of gyration, and consistent SASA profiles, compared to other ligands and the control compound. Our computational prediction suggests that apigenin exhibits favorable multi-target interactions with BC-associated proteins. Thus, apigenin may represent a potential candidate for further investigation, particularly with respect to oncogenic signaling pathways involving key hub proteins. However, experimental validation through\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    studies is required to confirm these observations.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0338874","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T17:33:21Z","timestamp":1782408801000},"page":"e0338874","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["In silico screening and molecular analyses identify apigenin from Scutellaria barbata as a potent AKT1 inhibitor in breast cancer"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1546-0127","authenticated-orcid":true,"given":"Md. Maruf","family":"Khan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8588-943X","authenticated-orcid":true,"given":"Md. Arju","family":"Hossain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatematuz","family":"Zohora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md.","family":"Sohel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9274-1335","authenticated-orcid":true,"given":"Md. Faisal","family":"Amin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatematuz Zuhura","family":"Evamoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4861-0030","authenticated-orcid":true,"given":"M. Nazmul","family":"Hoque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"issue":"3","key":"pone.0338874.ref001","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"F Bray","year":"2024","journal-title":"CA: a cancer journal for clinicians"},{"issue":"3","key":"pone.0338874.ref002","doi-asserted-by":"crossref","first-page":"326","DOI":"10.15537\/1658-3175.8333","article-title":"Global cancer burden growing, amidst mounting need for services","volume":"45","author":"Cancer IAfRo","year":"2024","journal-title":"Saudi Med J"},{"issue":"6","key":"pone.0338874.ref003","first-page":"477","article-title":"Breast cancer statistics 2024","volume":"74","author":"AN Giaquinto","year":"2024","journal-title":"CA: a cancer journal for clinicians"},{"issue":"1","key":"pone.0338874.ref004","article-title":"Cancer statistics, 2024","volume":"74","author":"RL Siegel","year":"2024","journal-title":"CA: a cancer journal for clinicians"},{"key":"pone.0338874.ref005","doi-asserted-by":"crossref","first-page":"1405204","DOI":"10.3389\/fendo.2024.1405204","article-title":"Disease burden of breast cancer and risk factors in Europe 44 countries, 1990-2019: findings of the global burden of disease study 2019","volume":"15","author":"S Yu","year":"2024","journal-title":"Front Endocrinol (Lausanne)"},{"key":"pone.0338874.ref006","doi-asserted-by":"crossref","first-page":"103835","DOI":"10.1016\/j.breast.2024.103835","article-title":"Current and future burden of breast cancer in Asia: A GLOBOCAN data analysis for 2022 and 2050","volume":"79","author":"M Fu","year":"2025","journal-title":"Breast"},{"issue":"1","key":"pone.0338874.ref007","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1158\/0008-5472.CAN-24-1211","article-title":"Distant metastases of breast cancer resemble primary tumors in cancer cell composition but differ in immune cell phenotypes","volume":"85","author":"L Kuett","year":"2025","journal-title":"Cancer Res"},{"issue":"10087","key":"pone.0338874.ref008","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1016\/S0140-6736(16)32417-5","article-title":"HER2-positive breast cancer","volume":"389","author":"S Loibl","year":"2017","journal-title":"Lancet"},{"issue":"1","key":"pone.0338874.ref009","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41523-022-00468-0","article-title":"Triple negative breast cancer: pitfalls and progress","volume":"8","author":"P Zagami","year":"2022","journal-title":"NPJ Breast Cancer"},{"key":"pone.0338874.ref010","first-page":"525","article-title":"Diagnostic and prognostic biomarkers of luminal breast cancer: where are we now?","author":"A H\u00f6ller","year":"2023","journal-title":"Breast Cancer: Targets and Therapy"},{"issue":"3","key":"pone.0338874.ref011","doi-asserted-by":"crossref","DOI":"10.1097\/MD.0000000000036905","article-title":"Breast cancer: a review of risk factors and diagnosis","volume":"103","author":"EI Obeagu","year":"2024","journal-title":"Medicine (Baltimore)"},{"issue":"3","key":"pone.0338874.ref012","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1001\/jama.2018.19323","article-title":"Breast cancer treatment: a review","volume":"321","author":"AG Waks","year":"2019","journal-title":"JAMA"},{"issue":"7782","key":"pone.0338874.ref013","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/s41586-019-1730-1","article-title":"A view on drug resistance in cancer","volume":"575","author":"N Vasan","year":"2019","journal-title":"Nature"},{"issue":"5","key":"pone.0338874.ref014","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/nrc3261","article-title":"Intra-tumour heterogeneity: a looking glass for cancer?","volume":"12","author":"A Marusyk","year":"2012","journal-title":"Nature Reviews Cancer"},{"issue":"1","key":"pone.0338874.ref015","doi-asserted-by":"crossref","first-page":"17182","DOI":"10.1038\/s41598-024-65112-2","article-title":"In-silico study unveils potential phytocompounds in Andrographis paniculata against E6 protein of the high-risk HPV-16 subtype for cervical cancer therapy","volume":"14","author":"MA Islam","year":"2024","journal-title":"Sci Rep"},{"issue":"6","key":"pone.0338874.ref016","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0320550","article-title":"Computational investigation unveils pathogenic LIG3 non-synonymous mutations and therapeutic targets in acute myeloid leukemia","volume":"20","author":"MA Hossen","year":"2025","journal-title":"PLoS One"},{"issue":"1","key":"pone.0338874.ref017","doi-asserted-by":"crossref","first-page":"160","DOI":"10.2174\/1381612825666191216124310","article-title":"Scutellaria barbata: a review on chemical constituents, pharmacological activities and clinical applications","volume":"26","author":"Q Chen","year":"2020","journal-title":"Curr Pharm Des"},{"key":"pone.0338874.ref018","doi-asserted-by":"crossref","first-page":"112260","DOI":"10.1016\/j.jep.2019.112260","article-title":"A review of the ethnopharmacology, phytochemistry, pharmacology, and quality control of Scutellaria barbata D. Don","volume":"254","author":"L Wang","year":"2020","journal-title":"J Ethnopharmacol"},{"key":"pone.0338874.ref019","doi-asserted-by":"crossref","first-page":"1497664","DOI":"10.3389\/fpls.2024.1497664","article-title":"A comparative study of the quality differences and seasonal dynamics of flavonoids between the aerial parts and roots of Scutellaria barbata","volume":"15","author":"Y Cheng","year":"2024","journal-title":"Front Plant Sci"},{"issue":"1","key":"pone.0338874.ref020","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jep.2011.12.041","article-title":"Fighting fire with fire: poisonous Chinese herbal medicine for cancer therapy","volume":"140","author":"S Wang","year":"2012","journal-title":"J Ethnopharmacol"},{"key":"pone.0338874.ref021","doi-asserted-by":"crossref","first-page":"112929","DOI":"10.1016\/j.jep.2020.112929","article-title":"Scutellaria barbata and Hedyotis diffusa herb pair for breast cancer treatment: potential mechanism based on network pharmacology","volume":"259","author":"T-T Ma","year":"2020","journal-title":"J Ethnopharmacol"},{"issue":"5","key":"pone.0338874.ref022","doi-asserted-by":"crossref","first-page":"646","DOI":"10.3390\/ph15050646","article-title":"Drug design by pharmacophore and virtual screening approach","volume":"15","author":"D Giordano","year":"2022","journal-title":"Pharmaceuticals (Basel)"},{"key":"pone.0338874.ref023","doi-asserted-by":"crossref","first-page":"1465827","DOI":"10.3389\/fphar.2024.1465827","article-title":"Computational identification of Vernonia cinerea-derived phytochemicals as potential inhibitors of nonstructural protein 1 (NSP1) in dengue virus serotype-2","volume":"15","author":"MS Hossain","year":"2024","journal-title":"Front Pharmacol"},{"issue":"1","key":"pone.0338874.ref024","doi-asserted-by":"crossref","first-page":"7141","DOI":"10.1038\/s41598-025-91410-4","article-title":"High throughput screening identifies potential inhibitors targeting trimethoprim resistant DfrA1 protein in Klebsiella pneumoniae and Escherichia coli","volume":"15","author":"S Hasnat","year":"2025","journal-title":"Sci Rep"},{"key":"pone.0338874.ref025","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3389\/fphar.2019.00123","article-title":"Network pharmacology databases for traditional chinese medicine: review and assessment","volume":"10","author":"R Zhang","year":"2019","journal-title":"Front Pharmacol"},{"issue":"1","key":"pone.0338874.ref026","doi-asserted-by":"crossref","first-page":"28632","DOI":"10.1038\/s41598-025-14469-z","article-title":"Integrative metabolomics and system pharmacology reveal the antioxidant blueprint of Psoralea corylifolia","volume":"15","author":"AB Shah","year":"2025","journal-title":"Sci Rep"},{"issue":"19","key":"pone.0338874.ref027","doi-asserted-by":"crossref","first-page":"9497","DOI":"10.3390\/ijms26199497","article-title":"\u03b1-Glucosidase inhibition-guided network pharmacology and molecular docking reveal the antidiabetic potential of cichorium intybus as a functional food","volume":"26","author":"AB Shah","year":"2025","journal-title":"Int J Mol Sci"},{"issue":"1","key":"pone.0338874.ref028","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1186\/s12906-022-03587-0","article-title":"Scutellaria barbata D.Don (SBD) extracts suppressed tumor growth, metastasis and angiogenesis in Prostate cancer via PI3K\/Akt pathway","volume":"22","author":"D Sheng","year":"2022","journal-title":"BMC Complement Med Ther"},{"issue":"4","key":"pone.0338874.ref029","article-title":"Scutellaria Barbata inhibits epithelial-mesenchymal transformation through PI3K\/AKT and MDM2 thus inhibiting the proliferation, migration and promoting apoptosis of Cervical Cancer cells","volume":"20","author":"G Wang","year":"2025","journal-title":"PLoS One"},{"issue":"1","key":"pone.0338874.ref030","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1186\/s12935-021-02282-3","article-title":"Chemoprotective and chemosensitizing effects of apigenin on cancer therapy","volume":"21","author":"Z Nozhat","year":"2021","journal-title":"Cancer Cell Int"},{"issue":"2","key":"pone.0338874.ref031","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s00216-019-02238-7","article-title":"Flavonoid aglycone-oriented data-mining in high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry: efficient and targeted profiling of flavonoids in Scutellaria barbata","volume":"412","author":"Q Fu","year":"2020","journal-title":"Anal Bioanal Chem"},{"issue":"1","key":"pone.0338874.ref032","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3390\/biomedicines11010109","article-title":"Targeting PI3K\/AKT\/mTOR pathway in breast cancer: from biology to clinical challenges","volume":"11","author":"K Cerma","year":"2023","journal-title":"Biomedicines"},{"issue":"1","key":"pone.0338874.ref033","doi-asserted-by":"crossref","first-page":"470","DOI":"10.3390\/ijms22010470","article-title":"Apigenin, a partial antagonist of the Estrogen Receptor (ER), inhibits ER-positive breast cancer cell proliferation through akt\/FOXM1 signaling","volume":"22","author":"TH Pham","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"9","key":"pone.0338874.ref034","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1080\/01635581.2025.2521884","article-title":"PI3K\/AKT\/mTOR pathway in breast cancer pathogenesis and therapy: insights into phytochemical-based therapeutics","volume":"77","author":"AF Wali","year":"2025","journal-title":"Nutr Cancer"},{"issue":"6","key":"pone.0338874.ref035","doi-asserted-by":"crossref","first-page":"728","DOI":"10.2174\/1871520615666150304120643","article-title":"Apigenin and breast cancers: from chemistry to medicine","volume":"15","author":"SM Nabavi","year":"2015","journal-title":"Anticancer Agents Med Chem"},{"key":"pone.0338874.ref036","doi-asserted-by":"crossref","first-page":"116306","DOI":"10.1016\/j.jep.2023.116306","article-title":"Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula","volume":"309","author":"L Zhao","year":"2023","journal-title":"J Ethnopharmacol"},{"key":"pone.0338874.ref037","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1758-2946-6-13","article-title":"TCMSP: a database of systems pharmacology for drug discovery from herbal medicines","volume":"6","author":"J Ru","year":"2014","journal-title":"J Cheminform"},{"issue":"2","key":"pone.0338874.ref038","doi-asserted-by":"crossref","DOI":"10.1093\/pcp\/pcs186","article-title":"KNApSAcK-3D: a three-dimensional structure database of plant metabolites","volume":"54","author":"K Nakamura","year":"2013","journal-title":"Plant Cell Physiol"},{"key":"pone.0338874.ref039","doi-asserted-by":"crossref","first-page":"714628","DOI":"10.3389\/fphar.2021.714628","article-title":"Network pharmacology-based identification of key mechanisms of Xihuang Pill in the treatment of triple-negative breast cancer stem cells","volume":"12","author":"Y-Z Zhang","year":"2021","journal-title":"Front Pharmacol"},{"issue":"10","key":"pone.0338874.ref040","article-title":"Theoretical drug-likeness, pharmacokinetic and toxicities of phytotoxic terpenoids from the toxic plants-phytotoxins","volume":"8","author":"OK Didigwu","year":"2024","journal-title":"Tropical Journal of Natural Product Research"},{"key":"pone.0338874.ref041","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkae303","article-title":"ProTox 3.0: a webserver for the prediction of toxicity of chemicals","volume":"52","author":"P Banerjee","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"pone.0338874.ref042","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"A Daina","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pone.0338874.ref043","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkp937","article-title":"STITCH 2: an interaction network database for small molecules and proteins","volume":"38","author":"M Kuhn","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"pone.0338874.ref044","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gky868","article-title":"The comparative toxicogenomics database: update 2019","volume":"47","author":"AP Davis","year":"2019","journal-title":"Nucleic Acids Research"},{"key":"pone.0338874.ref045","doi-asserted-by":"crossref","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards suite: from gene data mining to disease genome sequence analyses","volume":"54","author":"G Stelzer","year":"2016","journal-title":"Curr Protoc Bioinformatics"},{"issue":"14","key":"pone.0338874.ref046","doi-asserted-by":"crossref","DOI":"10.1016\/j.heliyon.2024.e34544","article-title":"Pantothenate kinase: a promising therapeutic target against pathogenic Clostridium species","volume":"10","author":"S Hasnat","year":"2024","journal-title":"Heliyon"},{"key":"pone.0338874.ref047","doi-asserted-by":"crossref","DOI":"10.1016\/j.csbr.2024.100028","article-title":"In-silico identification and characterization of effector proteins in the rice blast pathogen Magnaporthe oryzae","volume":"2","author":"S Hasnat","year":"2025","journal-title":"Comput Struct Biotechnol Rep"},{"issue":"1","key":"pone.0338874.ref048","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"DW Huang","year":"2009","journal-title":"Nat Protoc"},{"issue":"1","key":"pone.0338874.ref049","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1093\/nar\/gkg034","article-title":"STRING: a database of predicted functional associations between proteins","volume":"31","author":"C von Mering","year":"2003","journal-title":"Nucleic Acids Res"},{"issue":"11","key":"pone.0338874.ref050","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"P Shannon","year":"2003","journal-title":"Genome Res"},{"key":"pone.0338874.ref051","first-page":"291","volume-title":"Cytoscape: software for visualization and analysis of biological networks. Data mining in proteomics: from standards to applications","author":"M Kohl","year":"2010"},{"issue":"3","key":"pone.0338874.ref052","doi-asserted-by":"crossref","first-page":"500461","DOI":"10.1016\/j.vacun.2025.500461","article-title":"Development of a novel multi-epitope vaccine candidate for Marburg virus applying advanced immunoinformatics strategies: A computational analysis","volume":"26","author":"MdN Mashrur","year":"2025","journal-title":"Vacunas"},{"issue":"2","key":"pone.0338874.ref053","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0316275","article-title":"Molecular screening and dynamics simulation reveal potential phytocompounds in Swertia chirayita targeting the UspA1 protein of Moraxella catarrhalis for COPD therapy","volume":"20","author":"MM Uddin","year":"2025","journal-title":"PLoS One"},{"key":"pone.0338874.ref054","article-title":"cytoHubba: identifying hub objects and sub-networks from complex interactome","volume":"8","author":"C-H Chin","year":"2014","journal-title":"BMC Syst Biol"},{"key":"pone.0338874.ref055","article-title":"PubChem 2025 update","volume":"53","author":"S Kim","year":"2025","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"pone.0338874.ref056","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1158\/1078-0432.CCR-10-2381","article-title":"Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma","volume":"17","author":"A De Luisi","year":"2011","journal-title":"Clin Cancer Res"},{"issue":"1","key":"pone.0338874.ref057","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1046\/j.1365-2249.2002.01954.x","article-title":"Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells","volume":"130","author":"JB Marriott","year":"2002","journal-title":"Clin Exp Immunol"},{"issue":"1","key":"pone.0338874.ref058","first-page":"630","article-title":"Resveratrol suppresses colon cancer growth by targeting the AKT\/STAT3 signaling pathway","volume":"43","author":"D Li","year":"2019","journal-title":"Int J Mol Med"},{"issue":"6","key":"pone.0338874.ref059","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0101070","article-title":"Biochemical and cellular evidence demonstrating AKT-1 as a binding partner for resveratrol targeting protein NQO2","volume":"9","author":"T Hsieh","year":"2014","journal-title":"PLoS One"},{"issue":"9","key":"pone.0338874.ref060","doi-asserted-by":"crossref","first-page":"4800","DOI":"10.1080\/07391102.2023.2222837","article-title":"Network pharmacology and multitarget analysis of Nigella sativa in the management of diabetes and obesity: a computational study","volume":"42","author":"M Saleem","year":"2024","journal-title":"J Biomol Struct Dyn"},{"issue":"5","key":"pone.0338874.ref061","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1093\/emboj\/16.5.989","article-title":"1.9 A crystal structure of interleukin 6: implications for a novel mode of receptor dimerization and signaling","volume":"16","author":"W Somers","year":"1997","journal-title":"EMBO J"},{"issue":"1","key":"pone.0338874.ref062","doi-asserted-by":"crossref","DOI":"10.1186\/s13321-014-0037-3","article-title":"Bringing the MMFF force field to the RDKit: implementation and validation","volume":"6","author":"P Tosco","year":"2014","journal-title":"J Cheminform"},{"key":"pone.0338874.ref063","article-title":"The RCSB protein data bank: integrative view of protein, gene and 3D structural information","volume":"45","author":"PW Rose","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"pone.0338874.ref064","volume-title":"Pharmacophore and ligand-based design with Biovia Discovery Studio\u00ae","author":"L Design","year":"2014"},{"issue":"2","key":"pone.0338874.ref065","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/bib\/2.2.195","article-title":"Swiss-PDB Viewer (Deep View)","volume":"2","author":"W Kaplan","year":"2001","journal-title":"Brief Bioinform"},{"issue":"3","key":"pone.0338874.ref066","article-title":"CASTpFold: Computed Atlas of Surface Topography of alpha-folded proteins","volume":"123","author":"B Ye","year":"2024","journal-title":"Biophysical Journal"},{"issue":"13","key":"pone.0338874.ref067","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera--a visualization system for exploratory research and analysis","volume":"25","author":"EF Pettersen","year":"2004","journal-title":"J Comput Chem"},{"issue":"1","key":"pone.0338874.ref068","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1021\/ci049885e","article-title":"LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters","volume":"45","author":"G Wolber","year":"2005","journal-title":"J Chem Inf Model"},{"issue":"7","key":"pone.0338874.ref069","doi-asserted-by":"crossref","first-page":"4291","DOI":"10.1021\/acs.jctc.1c00302","article-title":"OPLS4: improving force field accuracy on challenging regimes of chemical space","volume":"17","author":"C Lu","year":"2021","journal-title":"J Chem Theory Comput"},{"issue":"18","key":"pone.0338874.ref070","doi-asserted-by":"crossref","first-page":"184111","DOI":"10.1063\/5.0193281","article-title":"Novel barostat implementation for molecular dynamics","volume":"160","author":"J Janek","year":"2024","journal-title":"J Chem Phys"},{"key":"pone.0338874.ref071","doi-asserted-by":"crossref","unstructured":"Alekseenko A, P\u00e1ll S, Lindahl E. GROMACS on AMD GPU-based HPC platforms: using SYCL for performance and portability. In: Proceedings of the Cray User Group, 2024. p. 71\u201384. doi: 10.1145\/3725789.3725797","DOI":"10.1145\/3725789.3725797"},{"issue":"16","key":"pone.0338874.ref072","doi-asserted-by":"crossref","first-page":"9478","DOI":"10.1021\/acs.chemrev.9b00055","article-title":"End-point binding free energy calculation with MM\/PBSA and MM\/GBSA: strategies and applications in drug design","volume":"119","author":"E Wang","year":"2019","journal-title":"Chem Rev"},{"issue":"3","key":"pone.0338874.ref073","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1063\/1.1516801","article-title":"On the optimization of Gaussian basis sets","volume":"118","author":"GA Petersson","year":"2003","journal-title":"The Journal of Chemical Physics"},{"key":"pone.0338874.ref074","unstructured":"Garc\u00eda-Valverde M, Cordero N, de la Cal ES. GAUSSVIEW\u00ae as a tool for learning organic chemistry. In: EDULEARN15 proceedings, 2015."},{"issue":"12","key":"pone.0338874.ref075","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1080\/00268976.2011.569513","article-title":"Spectroscopic evaluation of the global hardness of the atoms","volume":"109","author":"N Islam","year":"2011","journal-title":"Molecular Physics"},{"key":"pone.0338874.ref076","doi-asserted-by":"crossref","first-page":"106535","DOI":"10.1016\/j.intimp.2020.106535","article-title":"Breast cancer: biology, biomarkers, and treatments","volume":"84","author":"K Barzaman","year":"2020","journal-title":"Int Immunopharmacol"},{"issue":"1","key":"pone.0338874.ref077","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40164-022-00363-1","article-title":"Breast cancer heterogeneity and its implication in personalized precision therapy","volume":"12","author":"L Guo","year":"2023","journal-title":"Exp Hematol Oncol"},{"key":"pone.0338874.ref078","doi-asserted-by":"crossref","first-page":"1405491","DOI":"10.3389\/fonc.2024.1405491","article-title":"Advancements and challenges in triple-negative breast cancer: a comprehensive review of therapeutic and diagnostic strategies","volume":"14","author":"N Xiong","year":"2024","journal-title":"Front Oncol"},{"issue":"3","key":"pone.0338874.ref079","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: advances and opportunities","volume":"20","author":"AG Atanasov","year":"2021","journal-title":"Nat Rev Drug Discov"},{"issue":"2","key":"pone.0338874.ref080","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0031964","article-title":"Acute exposure of apigenin induces hepatotoxicity in Swiss mice","volume":"7","author":"P Singh","year":"2012","journal-title":"PLoS One"},{"key":"pone.0338874.ref081","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.cbi.2018.09.003","article-title":"4\u2019-hydroxywogonin inhibits colorectal cancer angiogenesis by disrupting PI3K\/AKT signaling","volume":"296","author":"D Sun","year":"2018","journal-title":"Chem Biol Interact"},{"issue":"4","key":"pone.0338874.ref082","doi-asserted-by":"crossref","first-page":"4367","DOI":"10.1007\/s12013-025-01871-7","article-title":"The pharmacological spectrum of hispidulin: a thorough systematic review and meta-analysis","volume":"83","author":"A Singh","year":"2025","journal-title":"Cell Biochem Biophys"},{"key":"pone.0338874.ref083","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/B978-0-323-98367-9.00012-3","article-title":"In silico methods for the prediction of drug toxicity","volume-title":"Pharmacokinetics and Toxicokinetic Considerations","author":"K Rajpoot","year":"2022"},{"issue":"1","key":"pone.0338874.ref084","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/s41392-021-00828-5","article-title":"Targeting PI3K\/Akt signal transduction for cancer therapy","volume":"6","author":"Y He","year":"2021","journal-title":"Signal Transduct Target Ther"},{"issue":"3","key":"pone.0338874.ref085","first-page":"1997","article-title":"ERK\/MAPK signalling pathway and tumorigenesis","volume":"19","author":"Y-J Guo","year":"2020","journal-title":"Exp Ther Med"},{"issue":"1","key":"pone.0338874.ref086","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13402-019-00489-1","article-title":"The dual role of tumor necrosis factor-alpha (TNF-\u03b1) in breast cancer: molecular insights and therapeutic approaches","volume":"43","author":"D Cruceriu","year":"2020","journal-title":"Cell Oncol (Dordr)"},{"issue":"1","key":"pone.0338874.ref087","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1186\/s13287-025-04218-4","article-title":"The role of the mTOR pathway in breast cancer stem cells (BCSCs): mechanisms and therapeutic potentials","volume":"16","author":"C Zhang","year":"2025","journal-title":"Stem Cell Res Ther"},{"key":"pone.0338874.ref088","doi-asserted-by":"crossref","first-page":"866014","DOI":"10.3389\/fonc.2022.866014","article-title":"IL-6\/JAK\/STAT3 signaling in breast cancer metastasis: biology and treatment","volume":"12","author":"SG Manore","year":"2022","journal-title":"Front Oncol"},{"key":"pone.0338874.ref089","doi-asserted-by":"crossref","first-page":"584","DOI":"10.3389\/fonc.2020.00584","article-title":"Tumor necrosis factor \u03b1 blockade: an opportunity to tackle breast cancer","volume":"10","author":"MF Mercogliano","year":"2020","journal-title":"Front Oncol"},{"issue":"1","key":"pone.0338874.ref090","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s40203-023-00152-6","article-title":"Molecular docking appraisal of Dysphania ambrosioides phytochemicals as potential inhibitor of a key triple-negative breast cancer driver gene","volume":"11","author":"LO Anifowose","year":"2023","journal-title":"In Silico Pharmacol"},{"issue":"2","key":"pone.0338874.ref091","article-title":"Identification of natural phytochemicals as AKT2 inhibitors using molecular docking and dynamics simulations as potential cancer therapeutics","volume":"11","author":"JK Paul","year":"2025","journal-title":"Heliyon"},{"issue":"3","key":"pone.0338874.ref092","doi-asserted-by":"crossref","first-page":"265","DOI":"10.7150\/ijms.5344","article-title":"Pharmacophore modeling, virtual screening, and molecular docking studies for discovery of novel Akt2 inhibitors","volume":"10","author":"J Fei","year":"2013","journal-title":"Int J Med Sci"},{"issue":"2","key":"pone.0338874.ref093","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/nrd4486","article-title":"Applying thermodynamic profiling in lead finding and optimization","volume":"14","author":"G Klebe","year":"2015","journal-title":"Nat Rev Drug Discov"},{"issue":"3","key":"pone.0338874.ref094","doi-asserted-by":"crossref","first-page":"869","DOI":"10.3892\/ijo.2015.3306","article-title":"Akt inhibitors in cancer treatment: the long journey from drug discovery to clinical use (Review)","volume":"48","author":"GM Nitulescu","year":"2016","journal-title":"Int J Oncol"},{"issue":"9","key":"pone.0338874.ref095","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1021\/acs.jmedchem.5b01684","article-title":"Role of molecular dynamics and related methods in drug discovery","volume":"59","author":"M De Vivo","year":"2016","journal-title":"J Med Chem"},{"issue":"3","key":"pone.0338874.ref096","doi-asserted-by":"crossref","first-page":"3055","DOI":"10.1007\/s00289-022-04181-7","article-title":"A DFT study of vibrational spectra of 5-chlorouracil with molecular structure, HOMO-LUMO, MEPs\/ESPs and thermodynamic properties","volume":"80","author":"JS Singh","year":"2023","journal-title":"Polym Bull (Berl)"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0338874","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T17:33:43Z","timestamp":1782408823000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0338874"}},"subtitle":[],"editor":[{"given":"Zhiling","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":96,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0338874","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]}}}