{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T02:19:52Z","timestamp":1780366792278,"version":"3.54.1"},"reference-count":66,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T00:00:00Z","timestamp":1701734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Genetic abnormalities have been associated with primary aldosteronism, a major cause of secondary hypertension. This includes mutations in the KCNJ5 gene, which encodes G protein-gated inwardly rectifying K+ channel 4 (GIRK4). For example, the substitution of glycine with glutamic acid gives rise to the pathogenic GIRK4G151E mutation, which alters channel selectivity, making it more permeable to Na+ and Ca2+. While tertiapin and tertiapin-Q are well-known peptide inhibitors of the GIRK4WT channel, clinically, there is a need for the development of selective modulators of mutated channels, including GIRK4G151E. Using in silico methods, including homology modeling, protein\u2013peptide docking, ligand-binding site prediction, and molecular docking, we aimed to explore potential modulators of GIRK4WT and GIRK4G151E. Firstly, protein\u2013peptide docking was performed to characterize the binding site of tertiapin and its derivative to the GIRK4 channels. In accordance with previous studies, the peptide inhibitors preferentially bind to the GIRK4WT channel selectivity filter compared to GIRK4G151E. A ligand-binding site analysis was subsequently performed, resulting in the identification of two potential regions of interest: the central cavity and G-loop gate. Utilizing curated chemical libraries, we screened over 700 small molecules against the central cavity of the GIRK4 channels. Flavonoids, including luteolin-7-O-rutinoside and rutin, and the macrolides rapamycin and troleandomycin bound strongly to the GIRK4 channels. Similarly, xanthophylls, particularly luteoxanthin, bound to the central cavity with a strong preference towards the mutated GIRK4G151E channel compared to GIRK4WT. Overall, our findings suggest potential lead compounds for further investigation, particularly luteoxanthin, that may selectively modulate GIRK4 channels.<\/jats:p>","DOI":"10.3390\/molecules28247946","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T08:09:17Z","timestamp":1701763757000},"page":"7946","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification of Potential Modulators of a Pathogenic G Protein-Gated Inwardly Rectifying K+ Channel 4 Mutant: In Silico Investigation in the Context of Drug Discovery for Hypertension"],"prefix":"10.3390","volume":"28","author":[{"given":"Eleni","family":"Pitsillou","sequence":"first","affiliation":[{"name":"Epigenomic Medicine Laboratory at prospED Polytechnic, Carlton, VIC 3053, Australia"},{"name":"School of Science, STEM College, RMIT University, Melbourne, VIC 3001, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander N. O.","family":"Logothetis","sequence":"additional","affiliation":[{"name":"Epigenomic Medicine Laboratory at prospED Polytechnic, Carlton, VIC 3053, Australia"},{"name":"Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3031-3169","authenticated-orcid":false,"given":"Julia J.","family":"Liang","sequence":"additional","affiliation":[{"name":"Epigenomic Medicine Laboratory at prospED Polytechnic, Carlton, VIC 3053, Australia"},{"name":"School of Science, STEM College, RMIT University, Melbourne, VIC 3001, Australia"},{"name":"Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, 75 Commercial Road, Prahran, VIC 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7968-7375","authenticated-orcid":false,"given":"Assam","family":"El-Osta","sequence":"additional","affiliation":[{"name":"Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, 75 Commercial Road, Prahran, VIC 3004, Australia"},{"name":"Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia"},{"name":"Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China"},{"name":"Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, 3\/F Lui Che Woo Clinical Sciences Building, 30-32 Ngan Shing Street, Sha Tin, Hong Kong SAR, China"},{"name":"Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China"},{"name":"Biomedical Laboratory Science, Department of Technology, Faculty of Health, University College Copenhagen, 1799 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3569-2951","authenticated-orcid":false,"given":"Andrew","family":"Hung","sequence":"additional","affiliation":[{"name":"School of Science, STEM College, RMIT University, Melbourne, VIC 3001, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa S.","family":"AbuMaziad","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine Tucson, The University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9967-1546","authenticated-orcid":false,"given":"Tom C.","family":"Karagiannis","sequence":"additional","affiliation":[{"name":"Epigenomic Medicine Laboratory at prospED Polytechnic, Carlton, VIC 3053, Australia"},{"name":"Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia"},{"name":"Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, 75 Commercial Road, Prahran, VIC 3004, Australia"},{"name":"Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.31128\/AJGP-07-19-4995","article-title":"Screening for primary aldosteronism: How to adjust existing antihypertensive medications to avoid diagnostic errors","volume":"49","author":"Gurgenci","year":"2020","journal-title":"Aust. 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