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To fully exploit their therapeutic potential, and to continue studying their pathophysiological role, it is crucial to develop selective modulators for each of these two channels. Here, we present a computational study to identify the molecular determinants behind the selectivity of two recently reported K\n                    <jats:sub>Ca<\/jats:sub>\n                    2.2 modulators, namely, N\u2010(2,1,3\u2010benzoxadiazol\u20104\u2010yl)\u20103\u2010(4\u2010methoxybenzene\u20101\u2010sulfonamido)benzamide and N\u2010(2,1,3\u2010benzoxadiazol\u20104\u2010yl)\u20104\u2010(trifluoromethyl)benzamide. We leveraged a protocol combining in silico mutagenesis, molecular dynamics simulations, and protein\u2013ligand docking to analyse the pockets targeted by these ligands. We identified the Ser353\/Pro245 substitution to be the main driver of the distinct pocket shapes in K\n                    <jats:sub>Ca<\/jats:sub>\n                    2.2 and K\n                    <jats:sub>Ca<\/jats:sub>\n                    3.1 channels, ultimately defining modulator selectivity. This approach provides novel insights into the structural differences of this binding site across potassium channel subtypes, proposing potential selectivity determinants of the modulators targeting this pocket.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70299","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T05:49:27Z","timestamp":1784180967000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mutation\u2010Induced Pocket Deactivation: How Ser353\/Pro245 Alters K\n                    <sub>Ca<\/sub>\n                    2.2 vs. K\n                    <sub>Ca<\/sub>\n                    3.1 Ligand Selectivity"],"prefix":"10.1002","volume":"359","author":[{"given":"Matteo","family":"Gozzi","sequence":"first","affiliation":[{"name":"GRK 2515, Chemical Biology of Ion Channels (Chembion) University of M\u00fcnster M\u00fcnster Germany"},{"name":"Institute of Pharmaceutical and Medicinal Chemistry University of M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Massa","sequence":"additional","affiliation":[{"name":"GRK 2515, Chemical Biology of Ion Channels (Chembion) University of M\u00fcnster M\u00fcnster Germany"},{"name":"Institute of Pharmaceutical and Medicinal Chemistry University of M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Koch","sequence":"additional","affiliation":[{"name":"GRK 2515, Chemical Biology of Ion Channels (Chembion) University of M\u00fcnster M\u00fcnster Germany"},{"name":"Institute of Pharmaceutical and Medicinal Chemistry University of M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-84052-5"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010pharmtox\u2010010919\u2010023420"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.116.012864"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.9.5746"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aas9466"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.107733"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.4c01711"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14043"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2013.823161"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014\u20102999(99)00616\u20100"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010023\u201002679\u20109"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.25233"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2010.09.025"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2011.90"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.17345"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102141.2010.08520.x"},{"key":"e_1_2_8_18_1","unstructured":"Biossil 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