Identificación de potenciales blancos moleculares e inhibidores para el tratamiento de infecciones fúngicas con base en similitudes estructurales con proteínas del farmacoloma humano
Cargando...
Compartir
Fecha
Autores
Título de la revista
ISSN de la revista
Título del volumen
Editor
Documentos PDF
Resumen
Descripción
Esta investigación tuvo como objetivo identificar nuevos blancos terapéuticos y compuestos antifúngicos mediante una estrategia combinada de análisis computacional y ensayos experimentales, tomando como referencia las proteínas del farmacoloma humano. Este “farmacoloma” corresponde al conjunto de productos génicos humanos modulados por fármacos aprobados. Se exploraron dos enfoques principales: el reposicionamiento de fármacos (uso de medicamentos ya aprobados para nuevas indicaciones), y el cribado virtual (virtual screening) de proteínas fúngicas específicas como posibles blancos moleculares. En una primera etapa se seleccionaron proteínas del farmacoloma humano con información cristalográfica disponible. A través de análisis estructurales y de secuencia se caracterizaron sus sitios de unión, identificando los aminoácidos clave en las interacciones proteína-ligando. Este conjunto se comparó con proteomas completos de hongos patógenos de alta prioridad definidos por la Organización Mundial de la Salud, incluyendo Candida albicans, Aspergillus fumigatus, Histoplasma capsulatum y Fusarium oxysporum. Se identificaron múltiples proteínas con potencial terapéutico, basadas en la conservación de sus sitios activos. Posteriormente, se generaron modelos computacionales de proteínas fúngicas ortólogas (homólogas en diferentes especies) para evaluar la posible unión de inhibidores conocidos de proteínas humanas y detectar diferencias estructurales que permitan diseñar inhibidores específicos. Como modelo experimental se seleccionó H. capsulatum, agente causal de la histoplasmosis, enfermedad endémica en América y Colombia. Asimismo, se analizó la proteína MEK1 humana y sus ortólogos en H. capsulatum y F. oxysporum. Este último es responsable de la fusariosis, segunda causa de infecciones por mohos en humanos, cuya incidencia ha aumentado en los últimos años.
This research aimed to identify new therapeutic targets and antifungal compounds through a combined strategy of computational analysis and experimental assays, using the proteins of the human pharmacolome as reference. This human pharmacolome corresponds to the curated set of human gene products modulated by approved drugs. Two main approaches were explored: drug repurposing (using already approved medications for new indications), and virtual screening of specific fungal proteins as potential molecular targets. In the first stage, pharmacolome proteins with available crystallographic information were selected. Structural and sequence analyses were performed to characterize their binding sites, identifying key amino acids involved in protein–ligand interactions. This curated set was compared against complete proteomes of high-priority pathogenic fungi defined by the World Health Organization, including Candida albicans, Aspergillus fumigatus, Histoplasma capsulatum, and Fusarium oxysporum. Several proteins with therapeutic potential were identified based on the conservation of their active sites. Subsequently, computational models of fungal orthologs (homologous proteins across species) were generated to evaluate the possible binding of known inhibitors of human proteins and to detect structural differences that could enable the design of specific inhibitors. H. capsulatum was selected as the experimental model, as it is the causative agent of histoplasmosis, an endemic disease in the Americas and Colombia. In addition, the human protein MEK1 and its orthologs in H. capsulatum and F. oxysporum were analyzed. The latter is responsible for fusariosis, the second leading cause of mold infections in humans, whose incidence has significantly increased in recent years.
This research aimed to identify new therapeutic targets and antifungal compounds through a combined strategy of computational analysis and experimental assays, using the proteins of the human pharmacolome as reference. This human pharmacolome corresponds to the curated set of human gene products modulated by approved drugs. Two main approaches were explored: drug repurposing (using already approved medications for new indications), and virtual screening of specific fungal proteins as potential molecular targets. In the first stage, pharmacolome proteins with available crystallographic information were selected. Structural and sequence analyses were performed to characterize their binding sites, identifying key amino acids involved in protein–ligand interactions. This curated set was compared against complete proteomes of high-priority pathogenic fungi defined by the World Health Organization, including Candida albicans, Aspergillus fumigatus, Histoplasma capsulatum, and Fusarium oxysporum. Several proteins with therapeutic potential were identified based on the conservation of their active sites. Subsequently, computational models of fungal orthologs (homologous proteins across species) were generated to evaluate the possible binding of known inhibitors of human proteins and to detect structural differences that could enable the design of specific inhibitors. H. capsulatum was selected as the experimental model, as it is the causative agent of histoplasmosis, an endemic disease in the Americas and Colombia. In addition, the human protein MEK1 and its orthologs in H. capsulatum and F. oxysporum were analyzed. The latter is responsible for fusariosis, the second leading cause of mold infections in humans, whose incidence has significantly increased in recent years.