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One strategy to correct the prolonged QT interval is to design molecules that activate KCNQ1\/KCNE1 channels and restore the QT interval. However, there are currently no clinically approved KCNQ1\/KCNE1 activators. Polyunsaturated fatty acids (PUFAs) have been shown to be potent activators of KCNQ1\/KCNE1, increasing KCNQ1\/KCNE1 currents and shortening the action potential duration in human cardiomyocytes. However, PUFAs are unspecific and have many targets, including other cardiac ion channels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>In this study, Site Identification by Ligand Competitive Saturation was used in combination with electrophysiology to optimize compounds that bind to the PUFA binding sites, increasing both their potency and site specificity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Two compounds, Compound 1\u2010 linoleic acid (LIN) and Compound 2\u2010LIN, exhibited a more potent activation effect on KCNQ1\/KCNE1 channels than our previous PUFA analogues, with each compound demonstrating a distinct activation mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>These findings highlight the potential of computer\u2010aided drug design in developing more targeted and effective KCNQ1\/KCNE1 activators, paving the way for personalized therapeutic strategies in treating cardiac disorders. Although the small molecule screening identified compounds with favourable interactions at PUFA binding sites, a lipid tail was required for their effect. This strategy of incorporating lipid tails onto small molecules offers a novel approach for targeting the underexplored transmembrane regions of membrane proteins, which could significantly impact drug development for a wide range of therapeutic targets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70532","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T03:10:59Z","timestamp":1781579459000},"page":"5407-5420","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimization of novel compounds using computer\u2010aided drug design for treatment of cardiac arrhythmia"],"prefix":"10.1111","volume":"183","author":[{"given":"Jessica","family":"Jowais","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Miller School of Medicine University of Miami  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M.","family":"Castro\u2010Gonzalez","sequence":"additional","affiliation":[{"name":"Centre for Molecular Simulation and Department of Biological Sciences University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Golluscio","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Miller School of Medicine University of Miami  Miami Florida USA"},{"name":"Department of Biomedical and Clinical Sciences (BKV) Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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