دورية أكاديمية
Molecular Dynamic Simulations to Determine Individualized Therapy: Tetrabenazine for the GNAO1 Encephalopathy E246K Variant.
| العنوان: | Molecular Dynamic Simulations to Determine Individualized Therapy: Tetrabenazine for the GNAO1 Encephalopathy E246K Variant. |
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| المؤلفون: | Falsaperla R; Neonatal Intensive Care Unit and Neonatal Accompaniment Unit, Azienda Ospedaliero-Universitaria Policlinico 'Rodolico-San Marco', San Marco Hospital, University of Catania, Catania, Italy. raffaelefalsaperla@hotmail.com.; Unit of Clinical Paediatrics, Azienda Ospedaliero-Universitaria Policlinico, 'Rodolico-San Marco', San Marco Hospital, Catania, Italy. raffaelefalsaperla@hotmail.com.; Pediatric Clinic, University of Ferrara, Ferrara, Italy. raffaelefalsaperla@hotmail.com., Sortino V; Unit of Clinical Paediatrics, Azienda Ospedaliero-Universitaria Policlinico, 'Rodolico-San Marco', San Marco Hospital, Catania, Italy., Marino SD; Unit of Clinical Paediatrics, Azienda Ospedaliero-Universitaria Policlinico, 'Rodolico-San Marco', San Marco Hospital, Catania, Italy., Collotta AD; Unit of Clinical Paediatrics, Azienda Ospedaliero-Universitaria Policlinico, 'Rodolico-San Marco', San Marco Hospital, Catania, Italy.; Postgraduate Training Program in Pediatrics, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy., Gammeri C; Postgraduate Training Program in Pediatrics, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy., Sipala FM; Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy., Volti GL; Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 87, 95125, Catania, Italy., Ruggieri M; Unit of Clinical Pediatrics, Unit of Rare Diseases, AOU 'Policlinico', PO 'G. Rodolico', University of Catania, Catania, Italy., Ronsisvalle S; Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy. |
| المصدر: | Molecular diagnosis & therapy [Mol Diagn Ther] 2024 May; Vol. 28 (3), pp. 329-337. Date of Electronic Publication: 2024 Apr 06. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Adis, Springer International Country of Publication: New Zealand NLM ID: 101264260 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1179-2000 (Electronic) Linking ISSN: 11771062 NLM ISO Abbreviation: Mol Diagn Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Auckland : Adis, Springer International Original Publication: Auckland, N.Z. : Adis International, c2006- |
| مواضيع طبية MeSH: | Molecular Dynamics Simulation* , GTP-Binding Protein alpha Subunits, Gi-Go*/genetics , GTP-Binding Protein alpha Subunits, Gi-Go*/metabolism , Tetrabenazine*/therapeutic use, Humans ; Mutation ; Brain Diseases/drug therapy ; Brain Diseases/genetics ; Precision Medicine/methods ; Signal Transduction/drug effects |
| مستخلص: | Introduction: GNAO1 encephalopathy is characterized by severe hypotonia, psychomotor retardation, epilepsy, and movement disorders. Genetic variations in GNAO1 have been linked to neurological symptoms including movement disorders like dystonia. The correlation between the E246K mutation in the Gα subunit and aberrant signal transduction of G proteins has been established but no data are reported regarding the efficacy of medical treatment with tetrabenazine. Methods: Molecular modeling studies were performed to elucidate the molecular mechanisms underlying this mutation. We developed drug efficacy models using molecular dynamic simulations that replicated the behavior of wild-type and mutated proteins in the presence or absence of ligands. Results and Discussion: We demonstrated that the absence of the mutation leads to normal signal transduction upon receptor activation by the endogenous ligand, but not in the presence of tetrabenazine. In contrast, the presence of the mutation resulted in abnormal signal transduction in the presence of the endogenous ligand, which was corrected by the drug tetrabenazine. Tetrabenazine was identified as a promising therapeutic option for pediatric patients suffering from encephalopathy due to an E246K mutation in the GNAO1 gene validated through molecular dynamics. This is a potential first example of the use of this technique in a rare neurological pediatric disease. (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.) |
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| المشرفين على المادة: | EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go) Z9O08YRN8O (Tetrabenazine) 0 (GNAO1 protein, human) |
| تواريخ الأحداث: | Date Created: 20240406 Date Completed: 20240503 Latest Revision: 20240507 |
| رمز التحديث: | 20240507 |
| DOI: | 10.1007/s40291-024-00706-0 |
| PMID: | 38581611 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1179-2000 |
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| DOI: | 10.1007/s40291-024-00706-0 |