An In Silico Investigation of the Pathogenic G151R G Protein-Gated Inwardly Rectifying K+ Channel 4 Variant to Identify Small Molecule Modulators

Abstract

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 europaea, 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.