Búsqueda racional y análisis de actividad biológica de nuevos activadores del canal TRPV1, análogos a capsaicina
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Archivos
Fecha
2016
Autores
Profesor/a Guía
Facultad/escuela
Idioma
es
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Editor
Universidad Andrés Bello
Nombre de Curso
Licencia CC
Licencia CC
Resumen
La supervivencia de un organismo está directamente relacionada con su capacidad de
percibir e interpretar de manera adecuada su entorno. Esta tarea es realizada por el sistema
nervioso mediante la activación de un subgrupo de neuronas sensoriales primarias, las que
interpretan estos estímulos, transformándolos en impulsos nerviosos. Cuando un estímulo de
naturaleza química, mecánica o térmica supera un umbral de intensidad definido, se genera una
respuesta dolorosa aguda, proceso conocido como nocicepción. Durante décadas se utilizó a
capsaicina, compuesto picante del ají, como agente farmacológico específico para la
caracterización funcional de terminales sensoriales primarios. Su actividad selectiva sugería la
existencia de un receptor específico para este compuesto, lográndose la identificación de un canal relacionado a la familia de canales de potencial transiente (TRP) a partir de células del ganglio de la raíz dorsarl (DRG) de rata. Los receptores de potencial transiente o TRP se encuentran involucrados en procesos de transducción sensorial de prácticamente todos los organismos multicelulares, siendo el canal TRPV1 el primer miembro de esta familia en ser asociado a procesos de generación de dolor. La modulación de la actividad del canal por antagonistas y la insensibilización por la aplicación de agonistas de alta potencia, ha mostrado ser una estrategia efectiva para el tratamiento del dolor, pero no han sido fructíferas debido a los efectos adversos presentados en los individuos tratados. Esto abre la necesidad de la identificación mediante estrategias de búsqueda racional de nuevas moléculas, las que puedan servir como pistas para el desarrollo de terapias analgésicas mas eficaces y seguras. De este modo, tomando ventaja de las estructuras tridimensionales del canal TRPV1 publicadas, el presente estudio pretende aprovechar el poder de cómputo disponible para así aventurarnos en el desarrollo de una estrategia computacional, soportada con validación experimental, para la identificación de nuevos activadores del canal TRPV1 con el fin de aportar con nuevos compuestos líderes, más potentes que capsaicina, como punto de partida para la generación de nuevas terapias analgésicas.
Además, mediante la caracterización de los determinantes moleculares que median la interacción de ligandos agonistas con el canal, se espera continuar contribuyendo al entendimiento sobre el mecanismo de activación dependiente de ligando del canal TRPV1.
An organism survival is directly influenced by its capacity to perceive and interpret its surroundings in an adequate way. This task is performed by the nervous system, by activating a subgroup of primary sensory neurons, which interpret those stimuli, transforming them in an action potential. When a stimulus of chemical, mechanical or thermal nature surpasses a threshold of determined intensity it generates an acute pain response, process known as nociception. Capsaicin, the pungent compound of chili peppers, has been used for decades as a specific pharmacological agent for the functional characterization of primary sensory terminals. Its selective activity suggested the existence of a specific receptor for this compounds, allowing researchers to identify an ion channel related to the transient receptor potential (TRP) family from rat dorsal root ganglion (DRG) cells. The transient potential receptors or TRPs are involved in processes of sensory transduction in practically all multicellular organisms, being the TRPV1 ion channel the first member of this family to be associated to pain generation processes. Modulation of the channel`s activity by antagonists and insensitivity by high potency agonists has shown to be an effective strategy for pain alleviation, but hasn`t been fruitful due to the adverse effects seen in the treated individuals. This opens the necessity of identifying new molecules that could be leads for the development of more efficient and safer analgesic therapies through rational search strategies. In this way, using the tridimensional structures of the TRPV1 ion channel publicly available, this study aims to take advantage of the available computing capacity to adventure ourselves in the development of a computational strategy supported by an experimental validation for the identification of new activators of the TRPV1 ion channel to contribute with new leader compounds, more powerful than capsaicin, as starting points for generating new analgesic therapies. In addition, we hope to continue contributing to the understanding about the ligand dependent activation mechanism of the ion channel TRPV1 through the characterization of the molecular determinants that mediate the interaction of agonist ligands with the ion channel.
An organism survival is directly influenced by its capacity to perceive and interpret its surroundings in an adequate way. This task is performed by the nervous system, by activating a subgroup of primary sensory neurons, which interpret those stimuli, transforming them in an action potential. When a stimulus of chemical, mechanical or thermal nature surpasses a threshold of determined intensity it generates an acute pain response, process known as nociception. Capsaicin, the pungent compound of chili peppers, has been used for decades as a specific pharmacological agent for the functional characterization of primary sensory terminals. Its selective activity suggested the existence of a specific receptor for this compounds, allowing researchers to identify an ion channel related to the transient receptor potential (TRP) family from rat dorsal root ganglion (DRG) cells. The transient potential receptors or TRPs are involved in processes of sensory transduction in practically all multicellular organisms, being the TRPV1 ion channel the first member of this family to be associated to pain generation processes. Modulation of the channel`s activity by antagonists and insensitivity by high potency agonists has shown to be an effective strategy for pain alleviation, but hasn`t been fruitful due to the adverse effects seen in the treated individuals. This opens the necessity of identifying new molecules that could be leads for the development of more efficient and safer analgesic therapies through rational search strategies. In this way, using the tridimensional structures of the TRPV1 ion channel publicly available, this study aims to take advantage of the available computing capacity to adventure ourselves in the development of a computational strategy supported by an experimental validation for the identification of new activators of the TRPV1 ion channel to contribute with new leader compounds, more powerful than capsaicin, as starting points for generating new analgesic therapies. In addition, we hope to continue contributing to the understanding about the ligand dependent activation mechanism of the ion channel TRPV1 through the characterization of the molecular determinants that mediate the interaction of agonist ligands with the ion channel.
Notas
Tesis (Magíster en Biotecnología)
Proyecto FONDECYT Regular 1131003
Proyecto FONDECYT Regular 1131003
Palabras clave
Analgésicos, Canales Iónicos, Dolor