{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T20:59:46Z","timestamp":1792270786406,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013274","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000}}],"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Key Research and Development Program of China","award":["2021YFC2300800"],"award-info":[{"award-number":["2021YFC2300800"]}]},{"name":"Fund of Fudan University and Cao'ejiang Basic Research","award":["24FCA04"],"award-info":[{"award-number":["24FCA04"]}]},{"name":"Science and Technology Leading Talent Team in Inner Mongolia Autonomous Region","award":["2022LJRC0009"],"award-info":[{"award-number":["2022LJRC0009"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Schistosomiasis is a major neglected tropical disease that lacks an effective vaccine and faces increasing challenges from praziquantel resistance, underscoring the urgent need for novel therapeutics. Target-based drug discovery (TBDD) is a powerful strategy for drug development. In this study, we utilized AlphaFold to predict the structures of target proteins from <jats:italic><jats:italic>Schistosoma mansoni<\/jats:italic><\/jats:italic> and <jats:italic><jats:italic>S. japonicum<\/jats:italic><\/jats:italic>, followed by virtual molecular screening to identify potential inhibitors. Among 202 potential therapeutic targets, we identified 37 proteins with high-accuracy structural predictions suitable for molecular docking with 14,600 compounds. This screening yielded 268 candidate compounds, which were further evaluated <jats:italic><jats:italic>ex vivo<\/jats:italic><\/jats:italic> for activity against both adult and juvenile <jats:italic><jats:italic>S. mansoni<\/jats:italic><\/jats:italic> and <jats:italic><jats:italic>S. japonicum<\/jats:italic><\/jats:italic>. Seven compounds exhibited strong anti-schistosomal activity, with HY-B2171A (Carubicin hydrochloride, CH) emerging as the most potent. CH was predicted to target the splicing factor U2AF65, and knockdown of its coding gene <jats:italic><jats:italic>Smp_019690<\/jats:italic><\/jats:italic> resulted in a phenotype similar to CH treatment. RNA sequencing revealed that both CH treatment and <jats:italic><jats:italic>Smp_019690<\/jats:italic><\/jats:italic> RNA interference (RNAi) disrupted splicing events in the parasites. Further studies demonstrated that CH impairs parasite viability by inhibiting U2AF65 function in mRNA splicing regulation. By integrating RNAi-based target identification with structure-based virtual screening, alongside <jats:italic><jats:italic>ex vivo<\/jats:italic><\/jats:italic> phenotypic and molecular analyses of compound-treated schistosomes, our study provides a comprehensive framework for anti-schistosomal drug discovery and identifies promising candidates for further preclinical development.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013274","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T17:34:30Z","timestamp":1760376870000},"page":"e1013274","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Highly accurate protein structure prediction-based virtual docking pipeline accelerating the identification of anti-schistosomal compounds"],"prefix":"10.1371","volume":"21","author":[{"given":"Wenjun","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjie","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuepeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gongwen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oyetunde T.","family":"Oyeyemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0107-424X","authenticated-orcid":true,"given":"Jipeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"ppat.1013274.ref001","volume-title":"Schistosomiasis. 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