{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T04:57:50Z","timestamp":1789707470394,"version":"4.0.1"},"reference-count":68,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T00:00:00Z","timestamp":1732838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Primary aldosteronism is characterised by the excessive production of aldosterone, which is a key regulator of salt metabolism, and is the most common cause of secondary hypertension. Studies have investigated the association between primary aldosteronism and genetic alterations, with pathogenic mutations being identified. This includes a glycine-to-arginine substitution at position 151 (G151R) of the G protein-activated inward rectifier potassium (K+) channel 4 (GIRK4), which is encoded by the KCNJ5 gene. Mutations in GIRK4 have been found to reduce the selectivity for K+ ions, resulting in membrane depolarisation, the activation of voltage-gated Ca2+ channels, and an increase in aldosterone secretion. As a result, there is an interest in identifying and exploring the mechanisms of action of small molecule modulators of wildtype (WT) and mutant channels. In order to investigate the potential modulation of homotetrameric GIRK4WT and GIRK4G151R channels, homology models were generated. Molecular dynamics (MD) simulations were performed, followed by a cluster analysis to extract starting structures for molecular docking. The central cavity has been previously identified as a binding site for small molecules, including natural compounds. The OliveNetTM database, which consists of over 600 compounds from Olea\u00a0europaea, was subsequently screened against the central cavity. The binding affinities and interactions of the docked ligands against the GIRK4WT and GIRK4G151R channels were then examined. Based on the results, luteolin-7-O-rutinoside, pheophorbide a, and corosolic acid were identified as potential lead compounds. The modulatory activity of olive-derived compounds against the WT and mutated forms of the GIRK4 channel can be evaluated further in vitro.<\/jats:p>","DOI":"10.3390\/biology13120992","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T11:03:08Z","timestamp":1733310188000},"page":"992","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["An In Silico Investigation of the Pathogenic G151R G Protein-Gated Inwardly Rectifying K+ Channel 4 Variant to Identify Small Molecule Modulators"],"prefix":"10.3390","volume":"13","author":[{"given":"Eleni","family":"Pitsillou","sequence":"first","affiliation":[{"name":"Epigenomic Medicine Laboratory at prospED Polytechnic, Melbourne, VIC 3053, Australia"},{"name":"School of Science, STEM College, RMIT University, Melbourne, VIC 3001, 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, Melbourne, VIC 3053, Australia"},{"name":"Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noa","family":"Kino","sequence":"additional","affiliation":[{"name":"Epigenomic Medicine Laboratory at prospED Polytechnic, Melbourne, VIC 3053, Australia"},{"name":"Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2796-3576","authenticated-orcid":false,"given":"Jessica L.","family":"Lockwood","sequence":"additional","affiliation":[{"name":"Epigenomic Medicine Laboratory at prospED Polytechnic, Melbourne, VIC 3053, Australia"},{"name":"Department of Microbiology and Immunology, The University of Melbourne, Melbourne, 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, Melbourne, VIC 3004, Australia"},{"name":"Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, 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, 30-32 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, 2200 Copenhagen, Denmark"}],"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, Melbourne, VIC 3053, Australia"},{"name":"Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia"},{"name":"Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC 3010, Australia"},{"name":"Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, VIC 3010, Australia"},{"name":"Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1161\/HYPERTENSIONAHA.114.04636","article-title":"KCNJ5 Mutations Are the Most Frequent Genetic Alteration in Primary Aldosteronism","volume":"65","author":"Williams","year":"2015","journal-title":"Hypertension"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1152\/physrev.00030.2003","article-title":"Control of Aldosterone Secretion: A Model for Convergence in Cellular Signaling Pathways","volume":"84","author":"Hunyady","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1126\/science.1198785","article-title":"K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension","volume":"331","author":"Choi","year":"2011","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1161\/HYPERTENSIONAHA.124.22753","article-title":"Prevalence and Risk Factors for Secondary Hypertension in Young Adults","volume":"81","author":"Gardini","year":"2024","journal-title":"Hypertension"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/nrendo.2012.230","article-title":"Role of KCNJ5 in familial and sporadic primary aldosteronism","volume":"9","author":"Mulatero","year":"2013","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mourtzi, N., Sertedaki, A., Markou, A., Piaditis, G.P., and Charmandari, E. (2021). Unravelling the Genetic Basis of Primary Aldosteronism. Nutrients, 13.","DOI":"10.3390\/nu13030875"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"G1","DOI":"10.1093\/ejendo\/lvae041","article-title":"Familial hyperaldosteronism: An European Reference Network on Rare Endocrine Conditions clinical practice guideline","volume":"190","author":"Mulatero","year":"2024","journal-title":"Eur. J. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"107808","DOI":"10.1016\/j.pharmthera.2021.107808","article-title":"Therapeutic potential of targeting G protein-gated inwardly rectifying potassium (GIRK) channels in the central nervous system","volume":"223","author":"Jeremic","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1152\/physrev.00021.2009","article-title":"Inwardly rectifying potassium channels: Their structure, function, and physiological roles","volume":"90","author":"Hibino","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Cui, M., Xu, K., Gada, K.D., Shalomov, B., Ban, M., Eptaminitaki, G.C., Kawano, T., Plant, L.D., Dascal, N., and Logothetis, D.E. (2022). A novel small-molecule selective activator of homomeric GIRK4 channels. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.102009"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1210\/en.2013-1944","article-title":"Pharmacology and Pathophysiology of Mutated KCNJ5 Found in Adrenal Aldosterone-Producing Adenomas","volume":"155","author":"Tauber","year":"2014","journal-title":"Endocrinology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E155","DOI":"10.1210\/jc.2014-3009","article-title":"Novel KCNJ5 Mutations in Sporadic Aldosterone-Producing Adenoma Reduce Kir3.4 Membrane Abundance","volume":"100","author":"Cheng","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0337-9","article-title":"Genetic causes of primary aldosteronism","volume":"51","author":"Seidel","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1530\/ERC-17-0117","article-title":"Molecular characteristics of the KCNJ5 mutated aldosterone-producing adenomas","volume":"24","author":"Murakami","year":"2017","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1210\/jc.2008-0594","article-title":"A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism","volume":"93","author":"Geller","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1001\/archpedi.1959.02070020092012","article-title":"Primary aldosteronism due to adrenal hyperplasia; occurrence in a boy aged 10 years","volume":"98","author":"Therien","year":"1959","journal-title":"AMA J. Dis. Child."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1161\/HYPERTENSIONAHA.119.13476","article-title":"Primary Aldosteronism: KCNJ5 Mutations and Adrenocortical Cell Growth","volume":"74","author":"Yang","year":"2019","journal-title":"Hypertension"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1073\/pnas.1121407109","article-title":"Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5","volume":"109","author":"Scholl","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","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. J. Gen. Pract."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1111\/j.1476-5381.2011.01315.x","article-title":"Naringin directly activates inwardly rectifying potassium channels at an overlapping binding site to tertiapin-Q","volume":"163","author":"Yow","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3601","DOI":"10.1021\/bi002584n","article-title":"Titration of tertiapin-Q inhibition of ROMK1 channels by extracellular protons","volume":"40","author":"Ramu","year":"2001","journal-title":"Biochemistry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1172\/JCI91733","article-title":"Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma","volume":"127","author":"Scholl","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Karagiannis, T.C., Ververis, K., Liang, J.J., Pitsillou, E., Liu, S., Bresnehan, S.M., Xu, V., Wijoyo, S.J., Duan, X., and Ng, K. (2024). Identification and Evaluation of Olive Phenolics in the Context of Amine Oxidase Enzyme Inhibition and Depression: In Silico Modelling and In Vitro Validation. Molecules, 29.","DOI":"10.3390\/molecules29112446"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bonvino, N.P., Liang, J., McCord, E.D., Zafiris, E., Benetti, N., Ray, N.B., Hung, A., Boskou, D., and Karagiannis, T.C. (2018). OliveNet\u2122: A comprehensive library of compounds from Olea europaea. Database, 2018.","DOI":"10.1093\/database\/bay016"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Pitsillou, E., Liang, J.J., Beh, R.C., Prestedge, J., Catak, S., Hung, A., and Karagiannis, T.C. (2022). Identification of novel bioactive compounds from Olea europaea by evaluation of chemical compounds in the OliveNet\u2122 library: In silico bioactivity and molecular modelling, and in vitro validation of hERG activity. Comput. Biol. Med., 142.","DOI":"10.1016\/j.compbiomed.2022.105247"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pitsillou, E., Logothetis, A.N.O., Liang, J.J., El-Osta, A., Hung, A., AbuMaziad, A.S., and Karagiannis, T.C. (2023). 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. Molecules, 28.","DOI":"10.3390\/molecules28247946"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: Homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D523","DOI":"10.1093\/nar\/gkac1052","article-title":"UniProt: The Universal Protein Knowledgebase in 2023","volume":"51","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e60552","DOI":"10.7554\/eLife.60552","article-title":"Cryo-EM analysis of PIP(2) regulation in mammalian GIRK channels","volume":"9","author":"Niu","year":"2020","journal-title":"Elife"},{"key":"ref_30","unstructured":"(2022). The PyMOL Molecular Graphics System, Schr\u00f6dinger, LLC. 1.7.4.5 Edu."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/0010-4655(95)00042-E","article-title":"GROMACS: A message-passing parallel molecular dynamics implementation","volume":"91","author":"Berendsen","year":"1995","journal-title":"Comput. Phys. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1021\/ct300400x","article-title":"Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone \u03c6, \u03c8 and side-chain \u03c7(1) and \u03c7(2) dihedral angles","volume":"8","author":"Best","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based graphical user interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1002\/jcc.24829","article-title":"CHARMM-GUI ligand reader and modeler for CHARMM force field generation of small molecules","volume":"38","author":"Kim","year":"2017","journal-title":"J. Comput. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10096","DOI":"10.1063\/1.1808117","article-title":"A modified TIP3P water potential for simulation with Ewald summation","volume":"121","author":"Price","year":"2004","journal-title":"J. Chem. Phys."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1103\/PhysRevLett.45.1196","article-title":"Crystal Structure and Pair Potentials: A Molecular-Dynamics Study","volume":"45","author":"Parrinello","year":"1980","journal-title":"Phys. Rev. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H","article-title":"LINCS: A linear constraint solver for molecular simulations","volume":"18","author":"Hess","year":"1997","journal-title":"J. Comput. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: An N\u00b7log(N) method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1002\/(SICI)1521-3773(19990115)38:1\/2<236::AID-ANIE236>3.0.CO;2-M","article-title":"Peptide Folding: When Simulation Meets Experiment","volume":"38","author":"Daura","year":"1999","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"D1373","DOI":"10.1093\/nar\/gkac956","article-title":"PubChem 2023 update","volume":"51","author":"Kim","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminformatics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-1-4939-2269-7_19","article-title":"Small-molecule library screening by docking with PyRx","volume":"1263","author":"Dallakyan","year":"2015","journal-title":"Chem. Biol. Methods Protoc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"W593","DOI":"10.1093\/nar\/gkac389","article-title":"PrankWeb 3: Accelerated ligand-binding site predictions for experimental and modelled protein structures","volume":"50","author":"Jakubec","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Cui, M., Alhamshari, Y., Cantwell, L., Ei-Haou, S., Eptaminitaki, G.C., Chang, M., Abou-Assali, O., Tan, H., Xu, K., and Masotti, M. (2021). A benzopyran with antiarrhythmic activity is an inhibitor of Kir3.1-containing potassium channels. J. Biol. Chem., 296.","DOI":"10.1016\/j.jbc.2021.100535"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_50","unstructured":"Schr\u00f6dinger, L. (2022). Schr\u00f6dinger Release 2022-2: Maestro, Schr\u00f6dinger LLC."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1016\/j.bpj.2018.02.038","article-title":"Ensemble Docking in Drug Discovery","volume":"114","author":"Amaro","year":"2018","journal-title":"Biophys. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1124\/mol.117.111377","article-title":"Kir Channel Blockages by Proflavine Derivatives via Multiple Modes of Interaction","volume":"93","author":"Inanobe","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.neuropharm.2016.05.016","article-title":"Isolation of proflavine as a blocker of G protein-gated inward rectifier potassium channels by a cell growth-based screening system","volume":"109","author":"Kawada","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ejphar.2017.02.024","article-title":"Chloroquine blocks the Kir4.1 channels by an open-pore blocking mechanism","volume":"800","author":"Cui","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13321-018-0285-8","article-title":"P2Rank: Machine learning based tool for rapid and accurate prediction of ligand binding sites from protein structure","volume":"10","author":"Hoksza","year":"2018","journal-title":"J. Cheminformatics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s10557-021-07262-3","article-title":"The Effects of Verapamil, Hydralazine, and Doxazosin on Renin, Aldosterone, and the Ratio Thereof","volume":"37","author":"Veldhuizen","year":"2023","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1210\/jc.2015-4061","article-title":"The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline","volume":"101","author":"Funder","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"136712","DOI":"10.1016\/j.molstruc.2023.136712","article-title":"Diltiazem and Verapamil: Combined experimental and computational approaches to structural and spectroscopic characterization","volume":"1295","author":"Cinar","year":"2024","journal-title":"J. Mol. Struct."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Zubcevic, L., Wang, S., Bavro, V.N., Lee, S.-J., Nichols, C.G., and Tucker, S.J. (2015). Modular Design of the Selectivity Filter Pore Loop in a Novel Family of Prokaryotic \u2018Inward Rectifier\u2019 (NirBac) channels. Sci. Rep., 5.","DOI":"10.1038\/srep15305"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.tips.2014.06.002","article-title":"Altered and dynamic ion selectivity of K+ channels in cell development and excitability","volume":"35","author":"Chen","year":"2014","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1172\/JCI200415925","article-title":"Differential subunit composition of the G protein\u2013activated inward-rectifier potassium channel during cardiac development","volume":"114","author":"Fleischmann","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/S1097-2765(02)00659-7","article-title":"The (beta)gamma subunits of G proteins gate a K(+) channel by pivoted bending of a transmembrane segment","volume":"10","author":"Jin","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Subash-Babu, P., Abdulaziz AlSedairy, S., Abdulaziz Binobead, M., and Alshatwi, A.A. (2023). Luteolin-7-O-rutinoside Protects RIN-5F Cells from High-Glucose-Induced Toxicity, Improves Glucose Homeostasis in L6 Myotubes, and Prevents Onset of Type 2 Diabetes. Metabolites, 13.","DOI":"10.3390\/metabo13020269"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1007\/s00210-022-02266-8","article-title":"Luteolin-7-O-rutinoside from Pteris cretica L. var. nervosa attenuates LPS\/D-gal-induced acute liver injury by inhibiting PI3K\/AKT\/AMPK\/NF-\u03baB signaling pathway","volume":"395","author":"Xiong","year":"2022","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Saide, A., Lauritano, C., and Ianora, A. (2020). Pheophorbide a: State of the Art. Mar. Drugs, 18.","DOI":"10.3390\/md18050257"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"176564","DOI":"10.1016\/j.ejphar.2024.176564","article-title":"Corosolic acid attenuates platelet-derived growth factor signaling in macrophages and smooth muscle cells of pulmonary arterial hypertension","volume":"973","author":"Yamamura","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"104111","DOI":"10.1016\/j.pdpdt.2024.104111","article-title":"Effectiveness of Pheophorbide-a mediated Photodynamic Therapy against Doxorubicin Resistant Breast Cancer","volume":"46","author":"Sarbadhikary","year":"2024","journal-title":"Photodiagnosis Photodyn. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.jphs.2022.12.007","article-title":"Corosolic acid ameliorates vascular remodeling in pulmonary arterial hypertension via the downregulation of STAT3 signaling","volume":"151","author":"Kawade","year":"2023","journal-title":"J. Pharmacol. Sci."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/13\/12\/992\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:43:05Z","timestamp":1760114585000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/13\/12\/992"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,29]]},"references-count":68,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["biology13120992"],"URL":"https:\/\/doi.org\/10.3390\/biology13120992","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,29]]}}}