Diseño de moléculas alostéricas selectivas que modulen la función del receptor de glicina que porta la mutación R271Q causante de la enfermedad Hiperekplexia.
Loading...
Date
2025
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Universidad de Concepción
Abstract
La Hiperekplexia es una rara enfermedad neurológica que se caracteriza por una respuesta de sobresalto exagerado y una rigidez muscular grave generalizada o intermitente. Las mutaciones descritas en el gen GLRA1 producen la disfunción del GlyRα1 que lleva a un descontrol de la excitabilidad de la red neuronal. La mutación R271Q en RGliα1 no afecta la expresión del receptor en la membrana, pero altera la activación del canal por su agonista (glicina). A la fecha, se ha demostrado que propofol, un anestésico general intravenoso es capaz de recuperar la función en RGliα1 R271Q.
Dado este antecedente, este proyecto tiene como objetivo identificar nuevas moléculas capaces de restaurar la función del receptor de glicina mutante. Utilizando herramientas bioinformáticas, se empleó la estructura del receptor RGliα1 (PDB ID: 7M6S) para identificar una cavidad putativa asociada con la unión de propofol. Esta cavidad fue utilizada como base para el diseño de moléculas de novo. A continuación, se llevó a cabo un cribado virtual basado en la similitud de forma, utilizando diversas bases de datos. Las moléculas seleccionadas fueron filtradas según los resultados obtenidos en estudios de acoplamiento molecular y predicciones de energía libre de unión. Como resultado, se seleccionaron 11 moléculas candidatas, las cuales 6 moléculas fueron sometidas a evaluación experimental mediante registros electrofisiológicos. Los resultados obtenidos mostraron un potencial para la recuperación de la funcionalidad del receptor mutado.
Hyperekplexia is a rare neurological disorder characterized by an exaggerated startle response and severe, generalized or intermittent muscle stiffness. Mutations described in the GLRA1 gene lead to dysfunction of the GlyRα1 receptor, resulting in a loss of control over neuronal network excitability. The R271Q mutation in RGlyα1 does not affect receptor expression at the membrane but alters channel activation by its agonist (glycine). To date, it has been shown that propofol, an intravenous general anesthetic, is capable of restoring function in RGlyα1 R271Q. Given this background, the aim of this project is to identify new molecules capable of restoring the function of the mutant glycine receptor. Using bioinformatic tools, the structure of the RGlyα1 receptor (PDB ID: 7M6S) was used to identify a putative cavity associated with propofol binding. This cavity served as the basis for de novo molecule design. A virtual screening based on shape similarity was then carried out using various databases. The selected molecules were filtered according to the results obtained from molecular docking studies and predicted binding free energy. As a result, 11 candidate molecules were selected, of which 6 were subjected to experimental evaluation through electrophysiological recordings. The results showed potential for restoring the functionality of the mutated receptor.
Hyperekplexia is a rare neurological disorder characterized by an exaggerated startle response and severe, generalized or intermittent muscle stiffness. Mutations described in the GLRA1 gene lead to dysfunction of the GlyRα1 receptor, resulting in a loss of control over neuronal network excitability. The R271Q mutation in RGlyα1 does not affect receptor expression at the membrane but alters channel activation by its agonist (glycine). To date, it has been shown that propofol, an intravenous general anesthetic, is capable of restoring function in RGlyα1 R271Q. Given this background, the aim of this project is to identify new molecules capable of restoring the function of the mutant glycine receptor. Using bioinformatic tools, the structure of the RGlyα1 receptor (PDB ID: 7M6S) was used to identify a putative cavity associated with propofol binding. This cavity served as the basis for de novo molecule design. A virtual screening based on shape similarity was then carried out using various databases. The selected molecules were filtered according to the results obtained from molecular docking studies and predicted binding free energy. As a result, 11 candidate molecules were selected, of which 6 were subjected to experimental evaluation through electrophysiological recordings. The results showed potential for restoring the functionality of the mutated receptor.
Description
Tesis presentada para optar al grado de Magíster en Neurobiología.
Keywords
Enfermedades neuromusculares, Biomoléculas, Propofol