{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:15:08Z","timestamp":1785406508553,"version":"3.56.0"},"reference-count":49,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["101102733"],"award-info":[{"award-number":["101102733"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"award":["101102733"],"award-info":[{"award-number":["101102733"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dengue is the most common vector-borne viral disease worldwide, posing an increasing global health threat. Despite its high burden, no approved antiviral treatments or widely applicable vaccines exist, and patient management remains limited to supportive care, underscoring the urgent need for antiviral development. The NS5 protein is a prime antiviral target, owing to its crucial role in viral replication, high conservation across dengue virus (DENV) serotypes and lack of a human orthologue. We conducted a comprehensive sequence-to-structure analysis to identify conserved druggable regions within NS5, integrating large-scale sequence analysis with structural characterization across all four DENV serotypes. We identified four highly promising Consensus Druggable Pockets within the NS5 dimer\u2014CDP1d, CDP3d, CDP5d and CDP12d\u2014that overlap functionally critical regions, alongside 149 new potential hot spot residues. Domain-specific analysis revealed that MTase offers more densely conserved targets, whereas RdRp provides broader druggable surfaces, revealing complementary features for pharmacological modulation. Several identified pockets spatially overlap known inhibitor binding sites, and preliminary docking analyses support their capacity to accommodate small molecules, reinforcing their therapeutic relevance as candidate targets. Collectively, these findings provide a robust framework for the rational design of pan-serotype anti-DENV NS5 antivirals with an enhanced barrier to resistance.<\/jats:p>","DOI":"10.3390\/ijms27125639","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:09:17Z","timestamp":1782270557000},"page":"5639","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dengue Virus NS5 Target Discovery: A Comprehensive in Silico Exploration of Novel Druggable Sites for Pan-Serotype Antiviral Design"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0384-5319","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Trigueiro-Louro","sequence":"first","affiliation":[{"name":"Antiviral Resistance Lab, Research & Development Unit, Infectious Diseases Department, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, IP, Av. Padre Cruz, 1649-016 Lisbon, Portugal"},{"name":"Host-Pathogen Interaction Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal"},{"name":"Servi\u00e7o de Medicina, Hospital de S\u00e3o Francisco Xavier, Unidade Local de Sa\u00fade de Lisboa Ocidental (ULSLO), Estrada do Forte do Alto do Duque, 1449-005 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1619-1900","authenticated-orcid":false,"given":"Vanessa","family":"Correia","sequence":"additional","affiliation":[{"name":"Antiviral Resistance Lab, Research & Development Unit, Infectious Diseases Department, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, IP, Av. Padre Cruz, 1649-016 Lisbon, Portugal"},{"name":"Host-Pathogen Interaction Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inara dos Santos","family":"Ali","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interaction Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bulbul","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Antiviral Resistance Lab, Research & Development Unit, Infectious Diseases Department, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, IP, Av. Padre Cruz, 1649-016 Lisbon, Portugal"},{"name":"School of Agriculture, Galgotias University, Greater Noida 203201, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0138-0944","authenticated-orcid":false,"given":"Helena","family":"Rebelo-de-Andrade","sequence":"additional","affiliation":[{"name":"Antiviral Resistance Lab, Research & Development Unit, Infectious Diseases Department, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, IP, Av. Padre Cruz, 1649-016 Lisbon, Portugal"},{"name":"Host-Pathogen Interaction Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"ref_1","unstructured":"Pescador Ruschel, M., Panda, P., and Farmer, A. (2026, May 15). 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