{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T10:17:25Z","timestamp":1787480245363,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.pntd.0011303","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T00:00:00Z","timestamp":1684281600000}}],"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T00:00:00Z","timestamp":1682553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>Lymphatic filariasis is a debilitating illness with an estimated 50 million cases as of 2018. The majority of cases are caused by the parasitic worm<jats:italic>W<\/jats:italic>.<jats:italic>bancrofti<\/jats:italic>and additional cases by the worms<jats:italic>B<\/jats:italic>.<jats:italic>malayi<\/jats:italic>and<jats:italic>B<\/jats:italic>.<jats:italic>timori<\/jats:italic>. Dihydrofolate reductase (DHFR) is an established target in the treatment of cancer, bacterial, and protozoal infections and may be a potential target for drugs targeting parasitic worm infections, including filariasis. Recent studies have shown that known antifolate compounds, including methotrexate, inhibit the activity of<jats:italic>W<\/jats:italic>.<jats:italic>bancrofti<\/jats:italic>DHFR (<jats:italic>Wb<\/jats:italic>DHFR). However, the absence of structural information for filarial DHFRs has limited the study of more in-depth structure-function relationships. We report the structure of<jats:italic>Wb<\/jats:italic>DHFR complexed with NADPH and folate using X-ray diffraction data measured to 2.47 \u00c5 resolution. The structure of<jats:italic>Wb<\/jats:italic>DHFR reveals the usual DHFR fold and is currently only the second nematode DHFR structure in the Protein Data Bank. The equilibrium dissociation constants for NADPH (90 \u00b1 29 nM) and folate (23 \u00b1 4 nM) were determined by equilibrium titrations. The interactions of known antifolates with<jats:italic>Wb<\/jats:italic>DHFR were analyzed using molecular docking programs and molecular dynamics simulations. Antifolates with a hydrophobic core and extended linker formed favorable interactions with<jats:italic>Wb<\/jats:italic>DHFR. 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