Análisis in silico de compuestos de origen natural con actividad antagónica sobre el receptor 1 del neuropéptido S, en endometriosis
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Date
2024
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Universidad Nacional de Trujillo
Abstract
La endometriosis es una enfermedad que afecta a millones de mujeres e implica un cuadro clínico complejo, caracterizado por su relación con los mecanismos del dolor e inflamación. En la actualidad, el receptor 1 del neuropéptido S (NPSR1), es un nuevo objetivo terapéutico, pues la inhibición de la interacción con su ligando endógeno (neuropéptido S), desactiva sus vías metabólicas intracelulares, y la exacerbación de los síntomas antes descritos. Considerando a los productos naturales como una vasta fuente de moléculas bioactivas, la investigación analizó in silico a compuestos naturales con la finalidad de identificar aquellos con actividad antagónica sobre el receptor NPSR1. Para ello, se exportó moléculas de las bases de datos NPAtlas y NP_MRD, que presenten un fragmento molecular de SHA-68R; se calculó su actividad antagonista (pKB) mediante el análisis 2D-QSAR de sus descriptores moleculares, y seleccionó las más prometedoras para su análisis farmacodinámico sobre el receptor en estado activo e inactivo utilizando la aplicación AutoDockTools y Discovery Studio para la visualización 2D. Posterior al análisis, se seleccionó a la molécula 15, debido a su energía de afinidad de -8,7 kcal/mol, respaldada por sus múltiples enlaces de hidrógeno, y a la visualización 2D del mapa de sus interacciones. Los perfiles fisicoquímicos y farmacocinéticos de las moléculas seleccionadas determinaron que excedieron los límites permisibles, siendo común en moléculas naturales; no obstante, pueden servir como scaffolds y potenciarse, con la finalidad de contrarrestar esta enfermedad, para mejorar la calidad de vida de quienes la padecen.
ABSTRACT Endometriosis is a disease that affects millions of women and involves a complex clinical picture, characterized by its relationship with the mechanisms of pain and inflammation. Currently, neuropeptide S receptor 1 (NPSR1) is a new therapeutic target, since the inhibition of the interaction with its endogenous ligand (neuropeptide S), deactivates its intracellular metabolic pathways, and the exacerbation of the symptoms described above. Considering natural products as a vast source of bioactive molecules, the research analysed natural compounds in silico to identify those with antagonistic activity on NPSR1. To do this, molecules were exported from the NPAtlas and NP_MRD databases, which present a molecular fragment of SHA-68R; their antagonist activity (pKB) was calculated by 2D-QSAR analysis of their molecular descriptors, and the most promising ones were selected for pharmacodynamic analysis on the receptor in active and inactive state using the AutoDockTools application and Discovery Studio for 2D visualization. After the analysis, molecule 15 was selected, due to its affinity energy of -8,7 kcal/mol, supported by its multiple hydrogen bonds, and the 2D visualization of the map of its interactions. The physicochemical and pharmacokinetic profiles of the selected molecules determined that they exceeded the permissible limits, being common in natural molecules; however, they can serve as scaffolds and be enhanced, to counteract this disease, to improve the quality of life of those who suffer from it.
ABSTRACT Endometriosis is a disease that affects millions of women and involves a complex clinical picture, characterized by its relationship with the mechanisms of pain and inflammation. Currently, neuropeptide S receptor 1 (NPSR1) is a new therapeutic target, since the inhibition of the interaction with its endogenous ligand (neuropeptide S), deactivates its intracellular metabolic pathways, and the exacerbation of the symptoms described above. Considering natural products as a vast source of bioactive molecules, the research analysed natural compounds in silico to identify those with antagonistic activity on NPSR1. To do this, molecules were exported from the NPAtlas and NP_MRD databases, which present a molecular fragment of SHA-68R; their antagonist activity (pKB) was calculated by 2D-QSAR analysis of their molecular descriptors, and the most promising ones were selected for pharmacodynamic analysis on the receptor in active and inactive state using the AutoDockTools application and Discovery Studio for 2D visualization. After the analysis, molecule 15 was selected, due to its affinity energy of -8,7 kcal/mol, supported by its multiple hydrogen bonds, and the 2D visualization of the map of its interactions. The physicochemical and pharmacokinetic profiles of the selected molecules determined that they exceeded the permissible limits, being common in natural molecules; however, they can serve as scaffolds and be enhanced, to counteract this disease, to improve the quality of life of those who suffer from it.
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Keywords
Endometriosis. Receptor 1 del neuropéptido S. SHA-68R. Moléculas bioactivas. Modelado molecular