Búsqueda virtual y cálculo computacional de la energía libre de unión de posibles inhibidores análogos a la glucosamina para la enzima hexoquinasa 2

ilustraciones, diagramas, tablas

Autores:
Méndez Otálvaro, Edward Francisco
Tipo de recurso:
Fecha de publicación:
2021
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/80993
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/80993
https://repositorio.unal.edu.co/
Palabra clave:
570 - Biología::572 - Bioquímica
540 - Química y ciencias afines::541 - Química física
540 - Química y ciencias afines::547 - Química orgánica
Chemical inhibitors
Inhibidores químicos
Enzyme Inhibitors
Inhibidores enzimaticos
Descriptor molecular
HK2
Tamizaje virtual
Simulación molecular
QSAR
Virtual screening
Molecular descriptor
Molecular simulation
Rights
openAccess
License
Atribución-NoComercial-SinDerivadas 4.0 Internacional
id UNACIONAL2_20020c9031582d75ae5b90bf65cb4e00
oai_identifier_str oai:repositorio.unal.edu.co:unal/80993
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Búsqueda virtual y cálculo computacional de la energía libre de unión de posibles inhibidores análogos a la glucosamina para la enzima hexoquinasa 2
dc.title.translated.eng.fl_str_mv Virtual screening and computational binding free energy calculation of possible glucosamine-like inhibitors for the enzyme hexokinase 2
title Búsqueda virtual y cálculo computacional de la energía libre de unión de posibles inhibidores análogos a la glucosamina para la enzima hexoquinasa 2
spellingShingle Búsqueda virtual y cálculo computacional de la energía libre de unión de posibles inhibidores análogos a la glucosamina para la enzima hexoquinasa 2
570 - Biología::572 - Bioquímica
540 - Química y ciencias afines::541 - Química física
540 - Química y ciencias afines::547 - Química orgánica
Chemical inhibitors
Inhibidores químicos
Enzyme Inhibitors
Inhibidores enzimaticos
Descriptor molecular
HK2
Tamizaje virtual
Simulación molecular
QSAR
Virtual screening
Molecular descriptor
Molecular simulation
title_short Búsqueda virtual y cálculo computacional de la energía libre de unión de posibles inhibidores análogos a la glucosamina para la enzima hexoquinasa 2
title_full Búsqueda virtual y cálculo computacional de la energía libre de unión de posibles inhibidores análogos a la glucosamina para la enzima hexoquinasa 2
title_fullStr Búsqueda virtual y cálculo computacional de la energía libre de unión de posibles inhibidores análogos a la glucosamina para la enzima hexoquinasa 2
title_full_unstemmed Búsqueda virtual y cálculo computacional de la energía libre de unión de posibles inhibidores análogos a la glucosamina para la enzima hexoquinasa 2
title_sort Búsqueda virtual y cálculo computacional de la energía libre de unión de posibles inhibidores análogos a la glucosamina para la enzima hexoquinasa 2
dc.creator.fl_str_mv Méndez Otálvaro, Edward Francisco
dc.contributor.advisor.none.fl_str_mv Barragán Ramírez, Daniel Alberto
Lans Vargas, Isaías
dc.contributor.author.none.fl_str_mv Méndez Otálvaro, Edward Francisco
dc.contributor.researchgroup.spa.fl_str_mv Calorimetría y Termodinámica de Procesos Irreversibles
dc.subject.ddc.spa.fl_str_mv 570 - Biología::572 - Bioquímica
540 - Química y ciencias afines::541 - Química física
540 - Química y ciencias afines::547 - Química orgánica
topic 570 - Biología::572 - Bioquímica
540 - Química y ciencias afines::541 - Química física
540 - Química y ciencias afines::547 - Química orgánica
Chemical inhibitors
Inhibidores químicos
Enzyme Inhibitors
Inhibidores enzimaticos
Descriptor molecular
HK2
Tamizaje virtual
Simulación molecular
QSAR
Virtual screening
Molecular descriptor
Molecular simulation
dc.subject.lemb.none.fl_str_mv Chemical inhibitors
Inhibidores químicos
Enzyme Inhibitors
Inhibidores enzimaticos
dc.subject.proposal.spa.fl_str_mv Descriptor molecular
HK2
Tamizaje virtual
Simulación molecular
dc.subject.proposal.eng.fl_str_mv QSAR
Virtual screening
Molecular descriptor
Molecular simulation
description ilustraciones, diagramas, tablas
publishDate 2021
dc.date.issued.none.fl_str_mv 2021-11
dc.date.accessioned.none.fl_str_mv 2022-02-16T15:50:03Z
dc.date.available.none.fl_str_mv 2022-02-16T15:50:03Z
dc.type.spa.fl_str_mv Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv Text
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/TM
status_str acceptedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unal.edu.co/handle/unal/80993
dc.identifier.instname.spa.fl_str_mv Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv https://repositorio.unal.edu.co/
url https://repositorio.unal.edu.co/handle/unal/80993
https://repositorio.unal.edu.co/
identifier_str_mv Universidad Nacional de Colombia
Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv spa
language spa
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dc.publisher.branch.spa.fl_str_mv Universidad Nacional de Colombia - Sede Medellín
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spelling Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Barragán Ramírez, Daniel Albertodbb5947eb81e7b9976d404433e5932eaLans Vargas, Isaías000373cf4d94681b568fdf55503c2efbMéndez Otálvaro, Edward Francisco61199f75a0b7c15dbb70338d26294717Calorimetría y Termodinámica de Procesos Irreversibles2022-02-16T15:50:03Z2022-02-16T15:50:03Z2021-11https://repositorio.unal.edu.co/handle/unal/80993Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, diagramas, tablasLa hexoquinasa 2 (HK2) es una enzima con importancia terapéutica humana debido a su relación con des órdenes metabólicos como la diabetes y el desarrollo de células cancerosas (efecto Warburg), por tanto, debemos implementar estrategias para obtener inhibidores efectivos frente a ella. Se ha reportado en la literatura experimental, una serie de glucosaminas 2,6 disustituidas con capacidad de inhibir HK2. En esta tesis desarrollamos una estrategia computacional para identificar compuestos análogos a la glucosamina con potencial afinidad por HK2 utilizando como entrada la información estructural y actividad in vitro del reporte antes mencionado. Para ello realizamos un tamizaje virtual de una base de datos pública mediante relaciones cuantitativas estructura-actividad (QSAR), modelos farmacofóricos y acoplamiento (docking) molecular. Generamos cinco modelos QSAR con una correlación razonable entre las propiedades fisicoquímicas y la actividad biológica experimental (R2P ≥ 0,6. σ2 ≥ 0,6. RMSEP < 2,0 y 0,2 ≤ R2 LOO ≤ 0,6) e identificamos tres moléculas con potencial actividad inhibitoria contra la HK2 (3, 6 y 139 en la numeración de este trabajo). Calculamos la afinidad de estos ligandos mediante simulaciones de dinámica molecular acopladas al método MM-PB(GB)SA. La afinidad de la molécula 3 hacia HK2 es de 6,91 (5,98; 7,85) Kcal mol−1, la de la molécula 6 de -4,11 (-5,04; -3,17) Kcal mol−1 y la de la molécula 139 de 0,49 (-0,44; 1,43) Kcal mol−1. Estas afinidades se encuentran dentro de un rango de energías apropiado a un control negativo y positivo [-16,12 (-17,06; -15,18) Kcal mol−1 y 3,59 (2,66; 4,53) Kcal mol−1], con significancia estadística. La estrategia es confiable para identificar moléculas similares a la glucosamina con potencial capacidad inhibitoria para este sistema, dado que a través de tres estrategias distintas (QSAR, farmacóforo y docking molecular) conseguimos el mismo grupo de moléculas. Además, los resultados se complementan en su aproximación, ya que por un lado el farmacóforo generaliza las características fisicoquímicas idóneas de los ligandos presentadas por los QSAR; y por el otro, el docking molecular tiene en cuenta las interacciones con el receptor, permitiendo mejorar las limitaciones de cada método. Finalmente, describimos un modo de acción para el ligando 6 que se rige mayormente por interacción hidrofóbica, correspondiendo a un mecanismo alternativo presentado por el control positivo, el cual contrasta por presentar en su mayoría interacciones de tipo puente de hidrogeno con el receptor (en su contribución entálpica). (Texto tomado de la fuente)Hexokinase 2 (HK2) is an enzyme with human therapeutic importance due to its relationship with metabolic disorders such as diabetes and cancer cell growing (Warburg effect), therefore, we must implement strategies to obtain effective inhibitors against it. Recently, a series of 2,6-disubstituted glucosamines with the ability to inhibit HK2 have been reported in the experimental literature. In this thesis we developed a computational strategy to identify glucosamine analogues with potential affinity for HK2 using as input the structural information and in vitro activity from the aforementioned report. For this purpose, we performed a virtual screening of a public database using quantitative structure-activity relationships (QSAR), pharmacophoric models and molecular docking. We generated five QSAR models with reasonable correlation between physicochemical properties and experimental biological activity (R2 P ≥ 0,6. σ 2 ≥ 0,6. RMSEP < 2,0 y 0,2 ≤ R2 LOO ≤ 0,6) and identified three molecules with potential inhibitory activity against HK2 (3, 6 and 139 in the numbering of this work). We calculated the affinity of these ligands by molecular dynamics simulations coupled to the MM-PB(GB)SA method. The affinity of molecule 3 toward HK2 is 6,91 (5,98; 7,85) Kcal mol−1 , that of molecule 6 is -4,11 (-5,04; -3,17) Kcal mol−1 and that of molecule 139 is 0,49 (-0,44; 1,43) Kcal mol−1 . These affinities are within a range of energies appropriate to a negative and positive control [-16,12 (-17,06; -15,18) Kcal mol−1 and 3,59 (2,66; 4,53) Kcal mol−1 ], with statistical significance. The strategy is reliable for identifying glucosamine-like molecules with potential inhibitory capacity for this system, since through three different strategies (QSAR, pharmacophore and molecular docking) we obtained the same group of molecules. Moreover, the results complement each other in their approach, since on the one hand the pharmacophore generalizes the ideal physicochemical characteristics of the ligands presented by the QSARs; and on the other hand, molecular docking takes into account the interactions with the receptor, allowing us to improve the limitations of each method. Finally, we describe a mode of action for ligand 6 that is mostly governed by hydrophobic interaction, corresponding to an alternative mechanism presented by the positive control, which contrasts by presenting mostly hydrogen bridge type interactions with the receptor (in its enthalpic contribution).MaestríaMagíster en Ciencias - QuímicaModelamiento computacional de sistemas fisicoquímicosÁrea Curricular en Ciencias Naturalesxxi, 164 páginasapplication/pdfspaUniversidad Nacional de ColombiaMedellín - Ciencias - Maestría en Ciencias - QuímicaEscuela de químicaFacultad de CienciasUniversidad Nacional de Colombia - Sede Medellín570 - Biología::572 - Bioquímica540 - Química y ciencias afines::541 - Química física540 - Química y ciencias afines::547 - Química orgánicaChemical inhibitorsInhibidores químicosEnzyme InhibitorsInhibidores enzimaticosDescriptor molecularHK2Tamizaje virtualSimulación molecularQSARVirtual screeningMolecular descriptorMolecular simulationBúsqueda virtual y cálculo computacional de la energía libre de unión de posibles inhibidores análogos a la glucosamina para la enzima hexoquinasa 2Virtual screening and computational binding free energy calculation of possible glucosamine-like inhibitors for the enzyme hexokinase 2Trabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMAhn, K. 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Thermodynamics: an engineering approach; McGraw-hill New York, 2011; Vol. 5.EstudiantesInvestigadoresMaestrosORIGINAL1152698890.2022.pdf1152698890.2022.pdfTesis de Maestría en Ciencias - Químicaapplication/pdf31739534https://repositorio.unal.edu.co/bitstream/unal/80993/3/1152698890.2022.pdf80cbc813d41aaacb2dd2454ff3101525MD53LICENSElicense.txtlicense.txttext/plain; charset=utf-84074https://repositorio.unal.edu.co/bitstream/unal/80993/4/license.txt8153f7789df02f0a4c9e079953658ab2MD54THUMBNAIL1152698890.2022.pdf.jpg1152698890.2022.pdf.jpgGenerated Thumbnailimage/jpeg5076https://repositorio.unal.edu.co/bitstream/unal/80993/5/1152698890.2022.pdf.jpg56388602386e4e2a8bb922951c9cf8e2MD55unal/80993oai:repositorio.unal.edu.co:unal/809932024-08-03 23:10:01.253Repositorio Institucional Universidad Nacional de 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EVESURBIFBPUiBMQSBTRUNSRVRBUsONQSBHRU5FUkFMLiAqTEEgVEVTSVMgQSBQVUJMSUNBUiBERUJFIFNFUiBMQSBWRVJTScOTTiBGSU5BTCBBUFJPQkFEQS4gCgpBbCBoYWNlciBjbGljIGVuIGVsIHNpZ3VpZW50ZSBib3TDs24sIHVzdGVkIGluZGljYSBxdWUgZXN0w6EgZGUgYWN1ZXJkbyBjb24gZXN0b3MgdMOpcm1pbm9zLiBTaSB0aWVuZSBhbGd1bmEgZHVkYSBzb2JyZSBsYSBsaWNlbmNpYSwgcG9yIGZhdm9yLCBjb250YWN0ZSBjb24gZWwgYWRtaW5pc3RyYWRvciBkZWwgc2lzdGVtYS4KClVOSVZFUlNJREFEIE5BQ0lPTkFMIERFIENPTE9NQklBIC0gw5psdGltYSBtb2RpZmljYWNpw7NuIDE5LzEwLzIwMjEK

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