{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T12:37:09Z","timestamp":1786538229501,"version":"build-2736575974"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"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>\n                    Thymidylate synthase (TYMS) is an established colorectal cancer (CRC) target. We evaluated whether conserved active-site architecture between human TYMS and the bacterial homolog TYSY KLEP7 could support early cross-species TYMS-axis lead discovery within the antifolate landscape. AlphaFold3, Chai-1 complex modeling, crystal-structure cross-validation, docking, ligand strain energy, MM-GBSA rescoring, and explicit-solvent MD were integrated to compare pocket states and prioritize antifolate-like Compound 8. Modeling indicated that Compound 8 preserves an acidic folate-groove anchoring motif while tolerating species- and ligand-induced pocket variation. Phenotypic assays showed dose-dependent inhibition of CRC cell viability with preliminary NCM460 selectivity, whereas antibacterial activity against\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    was modest, with a MIC of 96 \u00b5M and bactericidal activity only at 4\u00d7 MIC after 24\u00a0h. Target-axis assays supported TYMS\/\n                    <jats:italic>thyA<\/jats:italic>\n                    engagement: siTYMS and AS-\n                    <jats:italic>thyA<\/jats:italic>\n                    reduced transcript levels, and Compound 8 inhibited crude-lysate TS activity with apparent AC\n                    <jats:sub>50<\/jats:sub>\n                    values of 7.8 \u00b5M in HCT116 and 13.2 \u00b5M in\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    . Overall, this work establishes an AI-enabled structure-to-phenotype framework and positions Compound 8 as an early antifolate-like TYMS-axis lead requiring purified-enzyme, ADME, safety, and antibacterial optimization studies.\n                  <\/jats:p>","DOI":"10.3389\/fcimb.2026.1816809","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:44:34Z","timestamp":1782452674000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Artificial intelligence-guided discovery of a lead compound with antifolate-like activity against bacterial and human thymidylate synthases"],"prefix":"10.3389","volume":"16","author":[{"given":"Yi-Lin","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University","place":["Quzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ming","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University","place":["Quzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1023\/a:1008379101017","article-title":"Pemetrexed: a multitargeted antifolate agent with promising activity in solid tumors","volume":"11","author":"Adjei","year":"2000","journal-title":"Ann. 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