{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T02:48:05Z","timestamp":1790563685791,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,8,27]]},"abstract":"<jats:p>\n                    Orthoflaviviruses such as West Nile virus (WNV), Zika virus (ZIKV), or dengue virus (DENV) represent a growing global health threat, with millions of annual infections and no approved antiviral therapies. Targeting host pathways represents an alternative antiviral strategy that may overcome limitations associated with direct\u2010acting antivirals, including resistance and narrow antiviral spectra. Neutral sphingomyelinase\u20102 (nSMase2) plays a central role in sphingolipid metabolism and has emerged as a host factor involved in the replication of several flaviviruses including WNV and ZIKV. Herein, we report a new family of thienopyrimidinone derivatives as nSMase2 inhibitors. A ligand\u2010based virtual screening (LBVS) campaign using DPTIP as a template ligand identified 13 candidates from over 5 million ZINC20 compounds, which were refined through ADMET\u2010properties prediction and molecular docking. Experimental evaluation identified compound\n                    <jats:bold>16<\/jats:bold>\n                    as a novel nSMase2 inhibitor. Rational design guided by computational affinity maps enabled the synthesis of several derivatives bearing a thienopyrimidinone core. These compounds inhibited nSMase2 and showed antiviral activity against WNV in cell\u2011based assays. These results identify thienopyrimidinone derivatives as a new scaffold for nSMase2 inhibition and support host\u2010directed modulation of sphingolipid metabolism as a promising strategy for the development of broad\u2010spectrum antivirals against flaviviruses.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70452","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:21:34Z","timestamp":1787199694000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ligand\u2011Based Virtual Screening Discovery of Thienopyrimidinone Derivatives as Allosteric nSMase2 Modulators and Antivirals Against West Nile Virus"],"prefix":"10.1002","volume":"21","author":[{"given":"Hadri\u00e1n","family":"\u00c1lvarez\u2010Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica y Biomedicina (IQMB CSIC)  Madrid 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