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The L protein, the catalytic subunit of this complex (L-RdRp), is well-characterized structurally and represents a highly promising target for the development of novel small-molecule drugs against RSV. Methods: To address the limitations of current QSAR-based virtual screening strategies for RSV L-RdRp inhibitor development, we established a multi-dimensional computer-aided drug screening framework integrating activity, toxicity, drug-likeness, and stability. Results: Two OECD-compliant 2D-QSAR models were developed and rigorously validated to predict inhibitory activity and cytotoxicity, respectively. The optimal inhibitory activity model exhibited strong statistical performance, with R2 = 0.8281, QLOO2= 0.7653, Rtest2= 0.8713, QFn2= 0.8594 \u223c 0.8837, CCCtest = 0.9301, MAEtest = 0.1966. Similarly, the best cytotoxicity model achieved R2= 0.8263, QLOO2 = 0.7422, Rtest2 = 0.8951, QFn2 = 0.8108~0.8530, CCCtest = 0.9081, MAEtest = 0.1685. Based on these models, a four-step screening workflow\u2014QSAR-based filtering and molecular docking (15,758 \u2192 2446 \u2192 162 \u2192 19 compounds), ADMET evaluation (19 \u2192 5), and molecular dynamics simulations (MDSs)\u2014was implemented to identify promising L-RdRp inhibitors. Conclusions: Ultimately, five candidate compounds were selected, all of which demonstrated predicted higher inhibitory activity, lower predicted cytotoxicity, a stable predicted binding mode, and favorable oral bioavailability compared with the reference drug remdesivir. These findings provide valuable in silico-derived lead candidates and a reliable computational workflow for identifying experimental L-RdRp inhibitors targeting RSV.<\/jats:p>","DOI":"10.3390\/ph19081142","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:13:17Z","timestamp":1784826797000},"page":"1142","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computational Identification of Potential RSV L-RdRp Inhibitors with Predicted Superior Activity and Safety Profiles over Remdesivir Using QSAR Modeling, Molecular Docking and Molecular Dynamics Simulations"],"prefix":"10.3390","volume":"19","author":[{"given":"Yini","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, The Fifth People\u2019s Hospital of Huai\u2019an, Huai\u2019an 223300, China"},{"name":"Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runqing","family":"Jia","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Chen","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3086-3787","authenticated-orcid":false,"given":"Fen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The Fifth People\u2019s Hospital of Huai\u2019an, Huai\u2019an 223300, China"},{"name":"Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China"},{"name":"Department of Laboratory Medicine, Yangzhou University Affiliated Huai\u2019an Hospital, Huai\u2019an 223300, China"},{"name":"Yangzhou University Huai\u2019an Medical Collaborative Innovation Center, Huai\u2019an 223300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2259-5431","authenticated-orcid":false,"given":"Guohui","family":"Sun","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"544","DOI":"10.3181\/00379727-92-22538","article-title":"Recovery of Cytopathogenic Agent from Chimpanzees with Coryza","volume":"92","author":"Blount","year":"1956","journal-title":"Proc. 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