{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:43:56Z","timestamp":1789073036723,"version":"build-2803163510"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T00:00:00Z","timestamp":1775952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shandong Province Technology Innovation Guidance Program","award":["YDZX2024122"],"award-info":[{"award-number":["YDZX2024122"]}]},{"name":"Jinan \u201c20 New Universities\u201d Funding Project","award":["20222812"],"award-info":[{"award-number":["20222812"]}]},{"name":"Shandong Traditional Chinese Medicine Science and Technology Project","award":["Q-2023023"],"award-info":[{"award-number":["Q-2023023"]}]},{"name":"Chinese Medicine State Administration: Mechanism analysis of Huangbai Liniment","award":["GDY-KJS-2023-027"],"award-info":[{"award-number":["GDY-KJS-2023-027"]}]},{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["ZR2023LZY027"],"award-info":[{"award-number":["ZR2023LZY027"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"award":["ZR2023LZY027"],"award-info":[{"award-number":["ZR2023LZY027"]}],"id":[{"id":"https:\/\/ror.org\/04aqat463","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Science and Technology Major Project of China","award":["2025ZD1801402"],"award-info":[{"award-number":["2025ZD1801402"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Respiratory syncytial virus (RSV) is a major pathogen responsible for severe lower respiratory tract infections in infants, the elderly, and immunocompromised individuals. Because the RSV F protein mediates viral entry and 15-lipoxygenase (15-LOX) amplifies virus-induced inflammatory responses, dual targeting of these proteins may provide both antiviral and anti-inflammatory benefits. In this study, we combined computational prediction with experimental validation to identify natural dual-target inhibitors from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP). A total of 13,131 natural compounds were screened by drug-likeness evaluation, molecular docking, ADME assessment, and molecular dynamics simulations, yielding 31 potential dual-target candidates with favorable drug-like properties. Among them, rhoeadine (MOL001473) maintained stable binding conformations with both targets throughout 100 ns simulations. In BEAS-2B cells, rhoeadine exhibited significant anti-RSV activity (EC50 = 1.82 \u00b5M), low cytotoxicity (IC50 = 34.50 \u00b5M), and a selectivity index (SI) of 18.97. Time-of-addition experiments suggested that rhoeadine primarily acts at the early stage of viral infection. Additionally, ELISA results indicated that rhoeadine significantly inhibited RSV-induced secretion of CCL5 and IL-6, highlighting its anti-inflammatory potential. In summary, this study identified rhoeadine as a promising natural compound with antiviral and anti-inflammatory activities against RSV. Computational analyses suggested its potential association with RSV F protein and 15-LOX, although direct target-level validation is still required.<\/jats:p>","DOI":"10.3390\/ijms27083448","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T08:49:02Z","timestamp":1776070142000},"page":"3448","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of a Potential Dual-Target Candidate Against RSV F Protein and 15-LOX from TCMSP: Integrating Virtual Screening, Molecular Dynamics, and Experimental Evaluation"],"prefix":"10.3390","volume":"27","author":[{"given":"Xinyi","family":"Zhou","sequence":"first","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Du","sequence":"additional","affiliation":[{"name":"Shandong Academy of Chinese Medicine, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Academy of Chinese Medicine, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengru","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shandong Academy of Chinese Medicine, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Ding","sequence":"additional","affiliation":[{"name":"Shandong Academy of Chinese Medicine, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Academy of Chinese Medicine, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonghao","family":"Fan","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Academy of Chinese Medicine, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/s41591-024-03431-7","article-title":"Impact of RSVpreF vaccination on reducing the burden of respiratory syncytial virus in infants and older adults","volume":"31","author":"Du","year":"2025","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1111\/mmi.15133","article-title":"Respiratory syncytial virus entry mechanism in host cells: A general overview","volume":"120","author":"Camacho","year":"2023","journal-title":"Mol. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1056\/NEJMoa2110275","article-title":"Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants","volume":"386","author":"Hammitt","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1128\/AAC.01497-15","article-title":"GS-5806 Inhibits a Broad Range of Respiratory Syncytial Virus Clinical Isolates by Blocking the Virus-Cell Fusion Process","volume":"60","author":"Perron","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1126\/science.adp2362","article-title":"Mutating a flexible region of the RSV F protein can stabilize the prefusion conformation","volume":"385","author":"Liang","year":"2024","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Pang, Y., Lu, H., Cao, D., Zhu, X., Long, Q., Tian, F., Long, X., and Li, Y. (2024). Efficacy, immunogenicity and safety of respiratory syncytial virus prefusion F vaccine: Systematic review and meta-analysis. BMC Public Health, 24.","DOI":"10.1186\/s12889-024-18748-8"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/mi.2013.71","article-title":"Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology","volume":"7","author":"Lai","year":"2014","journal-title":"Mucosal Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Miyata, J., Yokokura, Y., Moro, K., Arai, H., Fukunaga, K., and Arita, M. (2021). 12\/15-Lipoxygenase Regulates IL-33-Induced Eosinophilic Airway Inflammation in Mice. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.687192"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Liu, Z., Fan, P., Chen, M., Xu, Y., and Zhao, D. (2021). miRNAs and Leukotrienes in Respiratory Syncytial Virus Infection. Front. Pediatr., 9.","DOI":"10.3389\/fped.2021.602195"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.micpath.2017.05.045","article-title":"Evaluation of the expression level of 12\/15 lipoxygenase and the related inflammatory factors (CCL5, CCL3) in respiratory syncytial virus infection in mice model","volume":"109","author":"Salimi","year":"2017","journal-title":"Microb. Pathog."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13045-022-01310-7","article-title":"Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy","volume":"15","author":"Liu","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1056\/NEJMoa2107519","article-title":"Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes","volume":"385","author":"Davies","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1080\/17460441.2024.2390511","article-title":"Perspectives on current approaches to virtual screening in drug discovery","volume":"19","author":"Muegge","year":"2024","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"42412","DOI":"10.1038\/s41598-025-26473-4","article-title":"In-silico identification of novel Cis-aconitate decarboxylase inhibitors as potential anti-inflammatory agents using molecular docking and dynamics","volume":"15","author":"Khadem","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ali, I., Iqbal, M.N., Ibrahim, M., Haq, I.U., Alonazi, W.B., and Siddiqi, A.R. (2023). Computational exploration of novel ROCK2 inhibitors for cardiovascular disease management; insights from high-throughput virtual screening, molecular docking, DFT and MD simulation. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0294511"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"107811","DOI":"10.1016\/j.compbiolchem.2023.107811","article-title":"Ensemble-based, high-throughput virtual screening of potential inhibitor targeting putative farnesol dehydrogenase of Metisa plana (Lepidoptera: Psychidae)","volume":"103","author":"Zifruddin","year":"2023","journal-title":"Comput. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e1800022","DOI":"10.1002\/minf.201800022","article-title":"High-throughput Docking and Molecular Dynamics Simulations towards the Identification of Novel Peptidomimetic Inhibitors against CDC7","volume":"37","author":"Makhouri","year":"2018","journal-title":"Mol. Inform."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"W337","DOI":"10.1093\/nar\/gkx333","article-title":"ProteinsPlus: A web portal for structure analysis of macromolecules","volume":"45","author":"Bietz","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1007\/s11030-023-10643-5","article-title":"Structure based High-Throughput Virtual Screening, Molecular Docking and Molecular Dynamics Study of anticancer natural compounds against fimbriae (FimA) protein of Porphyromonas gingivalis in oral squamous cell carcinoma","volume":"28","author":"Singh","year":"2024","journal-title":"Mol. Divers."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s00894-023-05637-x","article-title":"Effect of preprocessing and simulation parameters on the performance of molecular docking studies","volume":"29","author":"Biasi","year":"2023","journal-title":"J. Mol. Model."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8147","DOI":"10.1038\/s41598-023-35192-7","article-title":"Discovery of andrographolide hit analog as a potent cyclooxygenase-2 inhibitor through consensus MD-simulation, electrostatic potential energy simulation and ligand efficiency metrics","volume":"13","author":"Jain","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_23","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":"Ru","year":"2014","journal-title":"J. Cheminform."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Aqeel, I., Bilal, M., Majid, A., and Majid, T. (2022). Hybrid Approach to Identifying Druglikeness Leading Compounds against COVID-19 3CL Protease. Pharmaceuticals, 15.","DOI":"10.3390\/ph15111333"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6900","DOI":"10.12998\/wjcc.v10.i20.6900","article-title":"Network pharmacology-based strategy for predicting therapy targets of Sanqi and Huangjing in diabetes mellitus","volume":"10","author":"Cui","year":"2022","journal-title":"World J. Clin. Cases"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8908","DOI":"10.1038\/s41598-024-59734-9","article-title":"Non-animal models for blood\u2013brain barrier permeability evaluation of drug-like compounds","volume":"14","author":"Dehnbostel","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Faramarzi, S., Kim, M.T., Volpe, D.A., Cross, K.P., Chakravarti, S., and Stavitskaya, L. (2022). Development of QSAR models to predict blood-brain barrier permeability. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1040838"},{"key":"ref_28","unstructured":"UniProt Consortium (2025). UniProt: The Universal Protein Knowledgebase in 2025. Nucleic Acids Res., 53, D609\u2013D617."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1093\/nar\/gkg520","article-title":"SWISS-MODEL: An automated protein homology-modeling server","volume":"31","author":"Schwede","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1056\/NEJMc2400983","article-title":"Nirsevimab for Prevention of RSV Hospitalizations in Infants","volume":"390","author":"Raghuveer","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e2024066393","DOI":"10.1542\/peds.2024-066393","article-title":"Nirsevimab Effectiveness Against Severe Respiratory Syncytial Virus Infection in the Primary Care Setting","volume":"155","author":"Arce","year":"2025","journal-title":"Pediatrics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/j.healun.2023.01.013","article-title":"A randomized controlled trial of presatovir for respiratory syncytial virus after lung transplant","volume":"42","author":"Gottlieb","year":"2023","journal-title":"J. Heart Lung Transplant."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e0120521","DOI":"10.1128\/JVI.01205-21","article-title":"Mechanism of Cross-Resistance to Fusion Inhibitors Conferred by the K394R Mutation in Respiratory Syncytial Virus Fusion Protein","volume":"95","author":"Tang","year":"2021","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"102587","DOI":"10.1016\/j.plefa.2023.102587","article-title":"15-lipoxygenase and cyclooxygenase expression profile and their related modulators in COVID-19 infection","volume":"197","author":"Kianfar","year":"2023","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Al-Karmalawy, A.A., Dahab, M.A., Metwaly, A.M., Elhady, S.S., Elkaeed, E.B., Eissa, I.H., and Darwish, K.M. (2021). Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of ACEIs Against SARS-CoV-2 Targeting the hACE2 Receptor. Front. Chem., 9.","DOI":"10.3389\/fchem.2021.661230"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3448\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T08:58:13Z","timestamp":1776070693000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3448"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,12]]},"references-count":35,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27083448"],"URL":"https:\/\/doi.org\/10.3390\/ijms27083448","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,12]]}}}