Identificación de inhibidores polifuncionales contra blancos moleculares usados en el tratamiento de obesidad y diabetes

dc.contributorLópez Vallejo, Fabián Harvey
dc.contributorPrieto Rodríguez, Juliet Angélica
dc.contributorProductos Naturales Vegetales Bioactivos y Quimica EcoIogica
dc.creatorOsorio Murillo, Luis Alberto
dc.date.accessioned2021-05-31T21:22:08Z
dc.date.available2021-05-31T21:22:08Z
dc.date.created2021-05-31T21:22:08Z
dc.date.issued2020
dc.identifierhttps://repositorio.unal.edu.co/handle/unal/79579
dc.identifierUniversidad Nacional de Colombia
dc.identifierRepositorio Institucional Universidad Nacional de Colombia
dc.identifierhttps://repositorio.unal.edu.co/
dc.description.abstractLa diabesidad, término acuñado para referirse a la íntima relación entre las enfermedades diabetes tipo 2 y obesidad, se ha convertido en una problemática de carácter mundial sin distinguir entre poblaciones adultas e infantiles. A nivel global se reporta que, en los últimos años, el 44 % de los casos de diabetes tipo 2, el 23 % de cardiopatía isquémica y cerca del 41 % de los reportes de cáncer son atribuibles al sobrepeso o la obesidad. De allí que surja la necesidad de emprender investigaciones encaminadas en la búsqueda de tratamientos polifuncionales para obesidad y diabetes tipo II por la alta relación de estas patologías con comorbilidades de diversa índole. Dentro de las estrategias de búsqueda de nuevos tratamientos para obesidad y diabetes tipo 2, se encuentra la inhibición de enzimas digestivas secretadas por el páncreas como α-glucosidasa (AG), α-amilasa (AA) y lipasa pancreática (LP), tres blancos terapéuticos que están ampliamente descritos a nivel estructural y funcional, lo que permite usarlos para el desarrollo de estudios in silico e in vitro. En este sentido, los productos naturales constituyen una de las fuentes prometedoras para emprender este tipo de estudios, debido a que están constituidos por sustancias con amplia diversidad química y múltiples propiedades biológicas, hecho que representa una ventaja para encontrar sustancias con acción multidiana. Existe una amplia evidencia de la acción de productos naturales de diversas fuentes en aproximaciones in silico de lo que significaría una inhibición de los blancos moleculares descritos anteriormente. En el presente trabajo se realizó un cribado virtual por acoplamiento molecular en los sitios catalíticos de las enzimas AG, AA y LP en la búsqueda de compuestos con una alta interacción en los sitios catalíticos de las dianas biológicas, empleando una base de datos de productos naturales obtenida a partir de librerías de productos naturales comerciales depositadas en la base de datos Zinc15 (Zinc15.docking.org). Para los estudios de cribado virtual, por acoplamiento molecular, se utilizaron tres programas AutoDock 4.2, AutoDock Vina 1.1.2 y Glide. Para la interpretación y análisis de resultados se utilizaron los programas Pymol y Free Maestro®. Los compuestos con potencial de inhibición polifuncional sobre los blancos moleculares fueron seleccionados por medio de un método de consenso y consolidación, posteriormente, a partir de un ensayo experimental preliminar con LP se identificó el potencial de las moléculas; y como último punto, aquellas moléculas con actividad polifuncional se tomaron como insumo para postular un modelo de farmacóforo cualitativo que explique la relación estructura actividad. Aquellas moléculas que resultaron promisorias pertenecen a diferentes categorías de metabolitos, interesantemente con mejores comportamientos que las moléculas de referencia frente a las enzimas de estudio, de esta manera se postula un grupo de moléculas con alta probabilidad de efectuar acción polifuncional.
dc.description.abstractDiabesity, a term coined to refer to the intimate relationship between type 2 diabetes diseases and obesity, has become a worldwide problem without distinguishing between adult and child populations. At a global level, it is reported that, in recent years, 44 % of type 2 diabetes cases, 23 % of ischemic heart disease, and about 41 % of cancer reports are attributable to overweight or obesity. Hence, the need arises to undertake research aimed at the search for polyfunctional treatments for obesity and type 2 diabetes due to the high relationship of these pathologies with comorbidities of various kinds. Among the search strategies for new treatments for obesity and type 2 diabetes, is the inhibition of digestive enzymes secreted by the pancreas such as α-glucosidase (AG), α-amylase (AA) and pancreatic lipase (LP), three targets therapeutics that are widely described at the structural and functional level, which allows them to be used for the development of in silico and in vitro studies. In this sense, natural products constitute one of the promising sources to undertake this type of study, because they are made up of substances with wide chemical diversity and multiple biological properties, a fact that represents an advantage in finding substances with multitarget action. There is ample evidence of the action of natural products from various sources in in silico approximations of what an inhibition of the molecular targets described above would mean. In the present work, a virtual screening was carried out by molecular docking in the catalytic sites of the enzymes AG, AA and LP in the search for compounds with high interactions in the catalytic sites of the biological targets, using a database of natural products obtained from libraries of commercial natural products deposited in the Zinc15 database (Zinc15.docking.org). For the virtual screening studies, by molecular docking, three programs AutoDock 4.2, AutoDock Vina 1.1.2 and Glide were used. For the interpretation and analysis of results, the Pymol and Free Maestro® programs were used. Compounds with polyfunctional inhibition potential on molecular targets were selected by means of a consensus and consolidation method. Later, from a preliminary experimental test with LP, the potential of the molecules was identified; and as a last point, those molecules with polyfunctional activity were taken as input to postulate a qualitative pharmacophore model that explains the structure-activity relationship. Those molecules that were promising to belong to different categories of metabolites, interestingly with better behaviors than the reference molecules compared to the study enzymes, in this way a group of molecules with a high probability of carrying out polyfunctional action is postulated.
dc.languagespa
dc.publisherUniversidad Nacional de Colombia
dc.publisherBogotá - Ciencias - Maestría en Ciencias - Química
dc.publisherDepartamento de Química
dc.publisherFacultad de Ciencias
dc.publisherBogotá
dc.publisherUniversidad Nacional de Colombia - Sede Bogotá
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dc.rightsAtribución-NoComercial-SinDerivadas 4.0 Internacional
dc.rightshttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleIdentificación de inhibidores polifuncionales contra blancos moleculares usados en el tratamiento de obesidad y diabetes
dc.typeTrabajo de grado - Maestría


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