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Despite their medicinal importance, the mode of action of these compounds is poorly understood. In a previous study we observed these compounds, as well as quinine and mefloquine, tightly bind the DNA cocaine\u2010binding aptamer. Here, we further explore the range of nucleic acid structures bound by these compounds. To gauge a wide range of binding affinities, we used isothermal titration calorimetry to explore high affinity binding (nM to tens of \u03bcM) and NMR spectroscopy to assay weak binding biding in the hundreds of micromolar range. We find that amodiaquine tightly binds all double stranded DNA structures explored. Mefloquine binds double stranded DNA duplex molecules tightly and weakly associates with a three\u2010way junction DNA construct. Quinine and chloroquine only weakly bind duplex DNA but do not tightly bind any of the DNA constructs explored. A simulation of the free energy of binding of these ligands to the Dickerson\u2010Drew dodecamer resulted in an excellent agreement between the simulated and experimental free energy. These results provide new insight into the DNA binding of clinically important antimalarial compounds and may play a role in future development of new antimalarials.<\/jats:p>","DOI":"10.1002\/cbic.202400116","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T09:29:41Z","timestamp":1714123781000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Amodiaquine Nonspecifically Binds Double Stranded and Three\u2010Way Junction DNA Structures"],"prefix":"10.1002","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6927-1154","authenticated-orcid":false,"given":"Sladjana","family":"Slavkovic","sequence":"first","affiliation":[{"name":"Department of Chemistry York University  4700 Keele St. Toronto Ontario Canada M3J 1P3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5580-1273","authenticated-orcid":false,"given":"Aron A.","family":"Shoara","sequence":"additional","affiliation":[{"name":"Department of Chemistry York University  4700 Keele St. Toronto Ontario Canada M3J 1P3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3086-9124","authenticated-orcid":false,"given":"Yunus A.","family":"Kaiyum","sequence":"additional","affiliation":[{"name":"Department of Chemistry York University  4700 Keele St. Toronto Ontario Canada M3J 1P3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zachary R.","family":"Churcher","sequence":"additional","affiliation":[{"name":"Department of Chemistry York University  4700 Keele St. Toronto Ontario Canada M3J 1P3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1082-5570","authenticated-orcid":false,"given":"Tao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chemistry McGill University  Montreal Quebec Canada H3A 0B8"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lena","family":"Simine","sequence":"additional","affiliation":[{"name":"Department of Chemistry McGill University  Montreal Quebec Canada H3A 0B8"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5573-4891","authenticated-orcid":false,"given":"Philip E.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Chemistry York University  4700 Keele St. Toronto Ontario Canada M3J 1P3"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,6,16]]},"reference":[{"key":"e_1_2_9_1_1","unstructured":"\u00a0"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.06.033"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.4172\/2161-0444.1000315"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01485"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2020.09.011"},{"key":"e_1_2_9_6_1","unstructured":"\u00a0"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2007.11.005"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2003.10.003"},{"key":"e_1_2_9_9_1","unstructured":"\u00a0"},{"key":"e_1_2_9_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.8b05795"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-6851(89)90141-2"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0169-4758(90)90215-P"},{"key":"e_1_2_9_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2787(66)90078-5"},{"key":"e_1_2_9_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.2c01119"},{"key":"e_1_2_9_15_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25031410"},{"key":"e_1_2_9_16_1","unstructured":"\u00a0"},{"key":"e_1_2_9_17_2","doi-asserted-by":"crossref","unstructured":"R. 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