{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T03:01:40Z","timestamp":1777863700151,"version":"3.51.4"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Integrative proteome-wide virtual screening offers a powerful route to discover broad-spectrum antivirals against emerging flaviviruses, for which no approved therapeutics currently exist. Here, we address this gap by constructing homology models of all structural and nonstructural proteins from Zika, Yellow Fever, West Nile, Saint Louis Encephalitis, and Usutu viruses. We applied a standardized pipeline\u2014combining sequence and structure based pocket prediction (Concavity), electrostatic profiling (APBS), and pharmacokinetic filtering (Lipinski\u2019s rules, ADMET)\u2014to generate high-confidence binding sites. A focused library of 160 natural product scaffolds and repurposed antivirals was then docked exhaustively (2,000 runs per pocket) using AutoDock4\/Vina, followed by clustering and ranking by binding energy. Comparative analyses (RMSD, PCA, RMSF) confirmed conserved core folds alongside virus-specific surface signatures, guiding grid definition. Among the 40 top-ranked scaffolds, several flavonoids exhibited dual-site binding to the NS5 polymerase and E glycoprotein across at least four viruses, while ribavirin and sofosbuvir engaged conserved catalytic motifs in NS3\/NS5, highlighting opportunities for combination strategies. Lead compounds such as myricetin (Estimated Kd \u2248 1.9 \u00b5M), temoporfin (Estimated Kd \u2248 1.2 nM), and aurintricarboxylic acid (Estimated Kd \u2248 1.9 \u00b5M) demonstrated favorable multitarget profiles. This integrative framework prioritizes robust candidates for experimental validation and optimization of panflaviviral therapeutics.<\/jats:p>","DOI":"10.3389\/fcimb.2026.1723132","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T05:30:03Z","timestamp":1777527003000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative proteome-wide structural analysis and high-throughput docking identify broad-spectrum antiviral scaffolds against Zika, Yellow Fever, West Nile, Saint Louis encephalitis, and Usutu viruses"],"prefix":"10.3389","volume":"16","author":[{"given":"Anderson Pereira","family":"Soares","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Evolution and Bioinformatics, Center for Biological Sciences, Department of Microbiology, University of S\u00e3o Paulo","place":["S\u00e3o Paulo, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9 Berndt","family":"Penteado","sequence":"additional","affiliation":[{"name":"Laboratory of Integration of Experimental and Computational Techniques, School of Pharmaceutical Sciences, University of S\u00e3o Paulo","place":["S\u00e3o Paulo, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Phillipe","family":"Teixeira","sequence":"additional","affiliation":[{"name":"State University of Santa Catarina (UDESC) \u2013 Center for Agricultural and Veterinary Sciences","place":["Santa Catarina, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor Nicodemo","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Postgraduate Studies in Biotechnoscience, ABC Federal University (UFABC)","place":["Santo Andr\u00e9, S\u00e3o Paulo, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodrigo Bentes","family":"Kato","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Computational Biology of Fungi, Department of Biochemistry nd Immunology, Federal University of Minas Gerais","place":["Belo Horizonte, Brazil"]},{"name":"Ministry of Health","place":["Bras\u00edlia, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miklos Maximiliano","family":"Bajay","sequence":"additional","affiliation":[{"name":"State University of Santa Catarina (UDESC) \u2013 Center for Agricultural and Veterinary Sciences","place":["Santa Catarina, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrique Goulart Trossini","family":"Gustavo","sequence":"additional","affiliation":[{"name":"Laboratory of Integration of Experimental and Computational Techniques, School of Pharmaceutical Sciences, University of S\u00e3o Paulo","place":["S\u00e3o Paulo, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caio Cesar de Melo","family":"Freire","sequence":"additional","affiliation":[{"name":"Evolutionary Bioinformatics Laboratory, Center for Biological and Health Sciences, Department of Genetics and Evolution, Federal University of S\u00e3o Carlos","place":["S\u00e3o Carlos, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel Ferreira","family":"de Lima Neto","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Evolution and Bioinformatics, Center for Biological Sciences, Department of Microbiology, University of S\u00e3o Paulo","place":["S\u00e3o Paulo, Brazil"]},{"name":"Laboratory of Immunobiology of Infectious Diseases, Department of Microbiology, Immunology, and Parasitology, Federal University of Santa Catarina","place":["Florian\u00f3polis, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"B2","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1137\/S003614450342061","article-title":"& Holst, M. 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