Academic Journal
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
| العنوان: | 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 |
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| المؤلفون: | Pitsillou, E., Logothetis, A.N.O., Liang, J.J., El-Osta, A., Hung, A., AbuMaziad, A.S., Karagiannis, T.C. |
| المساهمون: | Department of Pediatrics, College of Medicine Tucson, The University of Arizona |
| المصدر: | Molecules |
| بيانات النشر: | Multidisciplinary Digital Publishing Institute (MDPI) |
| سنة النشر: | 2023 |
| المجموعة: | The University of Arizona: UA Campus Repository |
| مصطلحات موضوعية: | GIRK4, hypertension, inwardly rectifying K + channels, pathogenic mutations, primary aldosteronism |
| الوصف: | 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–peptide docking, ligand-binding site prediction, and molecular docking, we aimed to explore potential modulators of GIRK4WT and GIRK4G151E. Firstly, protein–peptide 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. © 2023 by the authors. ; Open access journal ; This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1420-3049 |
| Relation: | Pitsillou, E.; Logothetis, A.N.O.; Liang, J.J.; El-Osta, A.; Hung, A.; AbuMaziad, A.S.; Karagiannis, T.C. 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 2023, 28, 7946. https://doi.org/10.3390/molecules28247946; http://hdl.handle.net/10150/671873; Molecules |
| DOI: | 10.3390/molecules28247946 |
| الاتاحة: | http://hdl.handle.net/10150/671873 https://doi.org/10.3390/molecules28247946 |
| Rights: | © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.E1DD2CAE |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 14203049 |
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| DOI: | 10.3390/molecules28247946 |