{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:59:07Z","timestamp":1787029147349,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,9]],"date-time":"2025-03-09T00:00:00Z","timestamp":1741478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Victorian Government\u2019s Operational Infrastructure Scheme"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The mineralocorticoid receptor (MR) is a steroid hormone receptor that plays a key role in regulating sodium and water homeostasis and blood pressure. MR antagonists are a guideline recommended for therapy for the treatment of hypertension and cardiovascular disease but can cause hyperkalaemia. Modelling was performed for binding of the endogenous ligands aldosterone and cortisol and MR antagonist spironolactone to the ligand binding domain (LBD) of the MR. A molecular docking screen of compounds that were structurally similar to known antagonists was performed, leading to the identification of two novel compounds, C79 and E67. Molecular dynamics (MD) assessed the dynamic interactions with C79, E76, endogenous ligands, and spironolactone with the MR ligand binding domain (LBD). Analysis of the protein backbone showed modest changes in the overall structure of the MR LBD in response to binding of antagonists, with movement in helix 12 consistent with previous observations. All ligands tested maintained stable binding within the MR LBD throughout the simulations. Hydrogen bond formation played a more prominent role in the binding of endogenous ligands compared to antagonists. MM-PBSA binding free energy calculations showed that all ligands had similar binding affinities, with binding facilitated by key residues within the binding site. The novel antagonists demonstrated similar binding properties to spironolactone, warranting further evaluation. This study provides insights into the molecular mechanisms of MR activation and inhibition, which can aid in the development of novel therapeutic strategies for cardiovascular diseases.<\/jats:p>","DOI":"10.3390\/molecules30061226","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T05:46:52Z","timestamp":1741585612000},"page":"1226","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["In Silico Investigation of Mineralocorticoid Receptor Antagonists: Insights into Binding Mechanisms and Structural Dynamics"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3031-3169","authenticated-orcid":false,"given":"Julia J.","family":"Liang","sequence":"first","affiliation":[{"name":"Epigenomic Medicine Laboratory at prospED Polytechnic, Carlton, VIC 3053, 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"}]},{"given":"Sara","family":"Cao","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\/0000-0003-3569-2951","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"}]},{"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":"Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC 3010, 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\u201332 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, 2200 Copenhagen, Denmark"}],"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":"Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, 75 Commercial Road, Prahran, VIC 3004, Australia"},{"name":"Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia"},{"name":"Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC 3010, Australia"},{"name":"Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0450-5375","authenticated-orcid":false,"given":"Morag J.","family":"Young","sequence":"additional","affiliation":[{"name":"Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, VIC 3010, Australia"},{"name":"Cardiovascular Endocrinology Laboratory, Discovery & Preclinical Domain, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia"},{"name":"Department of Medicine (Alfred Health), Central Clinical School, Monash University, Clayton, VIC 3004, Australia"},{"name":"Central Clinical School, Monash University, Melbourne, VIC 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e012","DOI":"10.1621\/nrs.05012","article-title":"The mineralocorticoid receptor: Insights into its molecular and (patho)physiological biology","volume":"5","author":"Viengchareun","year":"2007","journal-title":"Nucl. 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