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Here, we identify four LAT-1 ligands, including one chemically novel substrate, by comparative modeling, virtual screening, and experimental validation. These results may rationalize the enhanced brain permeability of two drugs, including the anticancer agent acivicin. Finally, two of our hits inhibited proliferation of a cancer cell line by distinct mechanisms, providing useful chemical tools to characterize the role of LAT-1 in cancer metabolism.<\/jats:p>","DOI":"10.1073\/pnas.1218165110","type":"journal-article","created":{"date-parts":[[2013,3,19]],"date-time":"2013-03-19T03:06:17Z","timestamp":1363662377000},"page":"5480-5485","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":171,"title":["Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1"],"prefix":"10.1073","volume":"110","author":[{"given":"Ethan G.","family":"Geier","sequence":"first","affiliation":[{"name":"Departments of aBioengineering and Therapeutic Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avner","family":"Schlessinger","sequence":"additional","affiliation":[{"name":"Departments of aBioengineering and Therapeutic Sciences and"},{"name":"California Institute for Quantitative Biosciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Fan","sequence":"additional","affiliation":[{"name":"Departments of aBioengineering and Therapeutic Sciences and"},{"name":"Pharmaceutical Chemistry,"},{"name":"California Institute for Quantitative Biosciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan E.","family":"Gable","sequence":"additional","affiliation":[{"name":"Pharmaceutical Chemistry,"},{"name":"Graduate Group in Biophysics, University of California, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Irwin","sequence":"additional","affiliation":[{"name":"Departments of aBioengineering and Therapeutic Sciences and"},{"name":"Pharmaceutical Chemistry,"},{"name":"California Institute for Quantitative Biosciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrej","family":"Sali","sequence":"additional","affiliation":[{"name":"Departments of aBioengineering and Therapeutic Sciences and"},{"name":"Pharmaceutical Chemistry,"},{"name":"California Institute for Quantitative Biosciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Giacomini","sequence":"additional","affiliation":[{"name":"Departments of aBioengineering and Therapeutic Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,3,18]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.37.23629"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2008.06.015"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.44.8.1491"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1016092525901"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1080\/10717540600559510"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2010.08.019"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604235"},{"key":"e_1_3_3_8_2","doi-asserted-by":"crossref","unstructured":"Kobayashi K et al. 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