Ensuncho Muñoz, Adolfo EnriqueBravo Rubio, Yarelys Patricia2022-07-222022-07-222022-07-21https://repositorio.unicordoba.edu.co/handle/ucordoba/6150In this work, potential inhibitors of Ebola virus transmission were designed by analyzing the binding site of the Niemann Pick C1 protein, by means of molecular docking. For this investigation, a study of the binding site of the protein with cholesterol was carried out using the programs protein plus and CASTp; Following this, the validation of the method was carried out using the Ligplot + and USCF Chimera software. Subsequently, molecules from other investigations were taken to study their interactions and based on this, new molecules were designed to which molecular coupling was applied to be able to choose the molecules with the best binding energies and finally a study was carried out on this selected group. Of the pharmacokinetic properties by means of Swiss ADME. Structures 18(a) and 22(b) presented the best results in the bioavailability radar, both present a high gastrointestinal absorption, comply with the Lipinski rules and their values are within the established parameters, thus considering these molecules with great potential as inhibitors of the Ebola virus.1. Introducción.....................................................................................................................................102. Antecedentes...................................................................................................................................122.1 Aspectos Bioquímicos................................................................................................................132.1.1 Filovirus.................................................................................................................................................132.1.2 El EBOV.................................................................................................................................................132.1.3 Proteína Niemann pick C1 (NPC1).......................................................................................142.1.4 Reglas de Lipinski................................................................................................................152.1.5 Propiedades farmacocinéticas (ADME).........................................................................162.1.6 Toxicidad..............................................................................................................................................172.1.7 Dosis tóxicas y clases de toxicidad....................................................................................182.2 Aspectos computacionales....................................................................................................182.2.1 Química Computacional..........................................................................................................182.2.2 Mecánica Molecular (MM).............................................................................................192.2.3 Campos de fuerza universales (UFF).....................................................................202.2.4 Diseño de fármacos asistido por computadora (DiFAC)..........................202.2.5 Acoplamiento Molecular.................................................................................................212.2.6 Paquete computacional Autodock Vina..............................................................233. Objetivos..............................................................................................................................................253.1 Objetivo General.............................................................................................................................253.2 Objetivo Específico........................................................................................................................254. Metodología.......................................................................................................................................254.1 Construcción y optimización de la geometría de los ligantes........................254.2 Acondicionamiento del dominio de la proteína NPC1.........................................264.3 Redocking molecular (Estudio de validación)...........................................................264.4 Acoplamiento molecular .........................................................................................................264.5 Análisis en Ligplus.........................................................................................................................284.6 Estudio ADME de las moléculas propuestas...............................................................284.7 Estudio teórico del riesgo de toxicidad de las estructuras propuestas (Mutagenicidad, Tumorigenicidad, Irritación y Reproducción)............................................................................................................................................285. Resultados y discusión................................................................................................................285.1 Construcción y optimización de la geometría de los ligantes.........................285.2 Acondicionamiento del dominio de la proteína NPC1..........................................325.3 Validación del método.................................................................................................................335.4 Modelado de acoplamiento molecular de la NPC1 y los ligandos.................355.5 Análisis de interacciones............................................................................................................385.6 Estudio de las propiedades farmacocinéticas (ADME)..........................................415.7 Estudio teórico del riesgo de toxicidad de las estructuras propuestas......466. Conclusiones y recomendaciones........................................................................................476.1 Conclusiones........................................................................................................................................476.2 Recomendaciones...........................................................................................................................48A. Anexos ...................................................................................................................................................48application/pdfspaCopyright Universidad de Córdoba, 2022Trabajo de grado - Pregradoinfo:eu-repo/semantics/openAccessAtribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)Acoplamiento MolecularÉbolaFármacosInhibidoresNiemann pick C1Docking molecularEbolaDrugsInhibitorsNiemann Pick C1