Design and discovery of new potential dual kinase back-pocket binders by fragmentation and virtual screening of natural products
The discovery of new and better drugs is a costly and slow process in which the identification of optimal preclinical candidates is often a difficult task. To overcome this drawback, fragment based drug design (FBDD), virtual screening (VS) and the use of natural products (NP) have become powerful s...
- Autores:
-
Vásquez Jiménez, Andrés Felipe
- Tipo de recurso:
- Doctoral thesis
- Fecha de publicación:
- 2020
- Institución:
- Universidad de los Andes
- Repositorio:
- Séneca: repositorio Uniandes
- Idioma:
- eng
- OAI Identifier:
- oai:repositorio.uniandes.edu.co:1992/48401
- Acceso en línea:
- http://hdl.handle.net/1992/48401
- Palabra clave:
- Cribado de alto rendimiento (Desarrollo de medicamentos) - Investigaciones
Desarrollo de medicamentos - Investigciones
Dinámica molecular - Investigaciones
Biomoléculas - Investigaciones
Proteínas quinasas activadas por mitógenos - Investigaciones
Dihidrofolato reductasa - Investigaciones
Cáncer - Medicamentos - Investigaciones
Ingeniería
- Rights
- openAccess
- License
- https://repositorio.uniandes.edu.co/static/pdf/aceptacion_uso_es.pdf
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dc.title.es_CO.fl_str_mv |
Design and discovery of new potential dual kinase back-pocket binders by fragmentation and virtual screening of natural products |
title |
Design and discovery of new potential dual kinase back-pocket binders by fragmentation and virtual screening of natural products |
spellingShingle |
Design and discovery of new potential dual kinase back-pocket binders by fragmentation and virtual screening of natural products Cribado de alto rendimiento (Desarrollo de medicamentos) - Investigaciones Desarrollo de medicamentos - Investigciones Dinámica molecular - Investigaciones Biomoléculas - Investigaciones Proteínas quinasas activadas por mitógenos - Investigaciones Dihidrofolato reductasa - Investigaciones Cáncer - Medicamentos - Investigaciones Ingeniería |
title_short |
Design and discovery of new potential dual kinase back-pocket binders by fragmentation and virtual screening of natural products |
title_full |
Design and discovery of new potential dual kinase back-pocket binders by fragmentation and virtual screening of natural products |
title_fullStr |
Design and discovery of new potential dual kinase back-pocket binders by fragmentation and virtual screening of natural products |
title_full_unstemmed |
Design and discovery of new potential dual kinase back-pocket binders by fragmentation and virtual screening of natural products |
title_sort |
Design and discovery of new potential dual kinase back-pocket binders by fragmentation and virtual screening of natural products |
dc.creator.fl_str_mv |
Vásquez Jiménez, Andrés Felipe |
dc.contributor.advisor.none.fl_str_mv |
González Barrios, Andrés Fernando Reyes Muñoz, Alejandro Duitama Castellanos, Jorge Alexander De Vivo, Marco |
dc.contributor.author.none.fl_str_mv |
Vásquez Jiménez, Andrés Felipe |
dc.contributor.jury.none.fl_str_mv |
Miscione, Gian Pietro Hernández Ortíz, Juan Pablo |
dc.subject.armarc.es_CO.fl_str_mv |
Cribado de alto rendimiento (Desarrollo de medicamentos) - Investigaciones Desarrollo de medicamentos - Investigciones Dinámica molecular - Investigaciones Biomoléculas - Investigaciones Proteínas quinasas activadas por mitógenos - Investigaciones Dihidrofolato reductasa - Investigaciones Cáncer - Medicamentos - Investigaciones |
topic |
Cribado de alto rendimiento (Desarrollo de medicamentos) - Investigaciones Desarrollo de medicamentos - Investigciones Dinámica molecular - Investigaciones Biomoléculas - Investigaciones Proteínas quinasas activadas por mitógenos - Investigaciones Dihidrofolato reductasa - Investigaciones Cáncer - Medicamentos - Investigaciones Ingeniería |
dc.subject.themes.none.fl_str_mv |
Ingeniería |
description |
The discovery of new and better drugs is a costly and slow process in which the identification of optimal preclinical candidates is often a difficult task. To overcome this drawback, fragment based drug design (FBDD), virtual screening (VS) and the use of natural products (NP) have become powerful strategies aimed at exploring the chemical space in silica more broadly and improving the likelihood of finding innovative lead molecules more quickly and cost-effectively. On the other hand, we currently know that Cycline-Dependent Kinase 2 (CDK2) and Vascular-Endothelial Growth Factor Receptor 2 (VEGFR2) are human enzymes with a key role in signaling pathways responsible for cell proliferation, angiogenesis and metastasis, widely recognized as traits associated with cancer. While there is no officially approved antineoplastic drug to date that targets these enzymes as its primary targets, both may adopt an "inactive" conformation in which a posterior allosteric pocket at the accessible active site has been reported as a highly strategic interaction target to achieve greater selectivity. As a result of our research, we demonstrated that a combined protocol of VS and natural product derived fragments (NPDF) was successful in designing a set of virtual dual CDK2/VEGFR2 inhibitor candidates. These compounds possess potentially innovative, diverse and potent chemical frameworks that can be taken to eventual rounds of synthesis, biochemical assays and structural analysis for optimization. The results of this thesis project are intended to contribute both to the generation of new computational methods and to the identification of bioactive compounds against cancer and many other diseases still rampant all around the world |
publishDate |
2020 |
dc.date.issued.none.fl_str_mv |
2020 |
dc.date.accessioned.none.fl_str_mv |
2021-02-18T12:12:33Z |
dc.date.available.none.fl_str_mv |
2021-02-18T12:12:33Z |
dc.type.spa.fl_str_mv |
Trabajo de grado - Doctorado |
dc.type.coarversion.fl_str_mv |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
dc.type.driver.spa.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
dc.type.coar.spa.fl_str_mv |
http://purl.org/coar/resource_type/c_db06 |
dc.type.content.spa.fl_str_mv |
Text |
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http://purl.org/redcol/resource_type/TD |
format |
http://purl.org/coar/resource_type/c_db06 |
dc.identifier.uri.none.fl_str_mv |
http://hdl.handle.net/1992/48401 |
dc.identifier.doi.none.fl_str_mv |
10.57784/1992/48401 |
dc.identifier.pdf.none.fl_str_mv |
u833731.pdf |
dc.identifier.instname.spa.fl_str_mv |
instname:Universidad de los Andes |
dc.identifier.reponame.spa.fl_str_mv |
reponame:Repositorio Institucional Séneca |
dc.identifier.repourl.spa.fl_str_mv |
repourl:https://repositorio.uniandes.edu.co/ |
url |
http://hdl.handle.net/1992/48401 |
identifier_str_mv |
10.57784/1992/48401 u833731.pdf instname:Universidad de los Andes reponame:Repositorio Institucional Séneca repourl:https://repositorio.uniandes.edu.co/ |
dc.language.iso.es_CO.fl_str_mv |
eng |
language |
eng |
dc.rights.uri.*.fl_str_mv |
https://repositorio.uniandes.edu.co/static/pdf/aceptacion_uso_es.pdf |
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info:eu-repo/semantics/openAccess |
dc.rights.coar.spa.fl_str_mv |
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https://repositorio.uniandes.edu.co/static/pdf/aceptacion_uso_es.pdf http://purl.org/coar/access_right/c_abf2 |
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dc.format.extent.es_CO.fl_str_mv |
263 hojas |
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dc.publisher.es_CO.fl_str_mv |
Uniandes |
dc.publisher.program.es_CO.fl_str_mv |
Doctorado en Ingeniería |
dc.publisher.faculty.es_CO.fl_str_mv |
Facultad de Ingeniería |
dc.source.es_CO.fl_str_mv |
instname:Universidad de los Andes reponame:Repositorio Institucional Séneca |
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Universidad de los Andes |
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spelling |
Al consultar y hacer uso de este recurso, está aceptando las condiciones de uso establecidas por los autores.https://repositorio.uniandes.edu.co/static/pdf/aceptacion_uso_es.pdfinfo:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2González Barrios, Andrés Fernandocc132031-adde-4342-ba8c-b406b8175e2b400Reyes Muñoz, Alejandro9e4d3f3f-d194-4692-aa8b-4497c83504ba400Duitama Castellanos, Jorge Alexander579ff412-de79-4c40-a3c9-02c47a5ad340400De Vivo, Marco17bb38e8-d361-44b1-8145-8189285a42a9500Vásquez Jiménez, Andrés Felipe10905500Miscione, Gian PietroHernández Ortíz, Juan Pablo2021-02-18T12:12:33Z2021-02-18T12:12:33Z2020http://hdl.handle.net/1992/4840110.57784/1992/48401u833731.pdfinstname:Universidad de los Andesreponame:Repositorio Institucional Sénecarepourl:https://repositorio.uniandes.edu.co/The discovery of new and better drugs is a costly and slow process in which the identification of optimal preclinical candidates is often a difficult task. To overcome this drawback, fragment based drug design (FBDD), virtual screening (VS) and the use of natural products (NP) have become powerful strategies aimed at exploring the chemical space in silica more broadly and improving the likelihood of finding innovative lead molecules more quickly and cost-effectively. On the other hand, we currently know that Cycline-Dependent Kinase 2 (CDK2) and Vascular-Endothelial Growth Factor Receptor 2 (VEGFR2) are human enzymes with a key role in signaling pathways responsible for cell proliferation, angiogenesis and metastasis, widely recognized as traits associated with cancer. While there is no officially approved antineoplastic drug to date that targets these enzymes as its primary targets, both may adopt an "inactive" conformation in which a posterior allosteric pocket at the accessible active site has been reported as a highly strategic interaction target to achieve greater selectivity. As a result of our research, we demonstrated that a combined protocol of VS and natural product derived fragments (NPDF) was successful in designing a set of virtual dual CDK2/VEGFR2 inhibitor candidates. These compounds possess potentially innovative, diverse and potent chemical frameworks that can be taken to eventual rounds of synthesis, biochemical assays and structural analysis for optimization. The results of this thesis project are intended to contribute both to the generation of new computational methods and to the identification of bioactive compounds against cancer and many other diseases still rampant all around the worldEl descubrimiento de nuevos y mejores medicamentos es un proceso costoso y lento en el que la identificación de candidatos preclínicos óptimos es a menudo una tarea difícil. Para superar este inconveniente, el diseño de fármacos basado en fragmentos (FBDD), el cribado virtual (VS) y el uso de productos naturales (NP) se han convertido en estrategias poderosas que tienen el propósito de explorar más ampliamente el espacio químico in silico y mejorar la probabilidad de encontrar moléculas líderes innovadoras en de manera más rápida y rentable. Por otra parte, sabemos actualmente que la Quinasa Dependiente de Ciclina 2 (CDK2) y el Receptor del Factor de Crecimiento Vascular-Endotelial 2 (VEGFR2) son enzimas humanas con un rol clave en vías de señalización responsables de la proliferación celular, la angiogénesis y la metástasis, ampliamente reconocidos como rasgos asociados al cáncer. Si bien no existe a la fecha un fármaco antineoplásico aprobado oficialmente dirigido contra estas enzimas como sus objetivos principales, ambas pueden adoptar una conformación "inactiva" en la que un bolsillo alostérico posterior en el sitio activo accesible se ha reportado como un blanco de interacción altamente estratégico para alcanzar una mayor selectividad. Como resultado de nuestra investigación, demostramos que un protocolo combinado de VS y fragmentos derivados de productos naturales (NPDF) fue exitoso para diseñar un conjunto de candidatos virtuales de inhibidores duales de CDK2/VEGFR2. Estos compuestos poseen armazones químicos potencialmente innovadores, diversos y potentes que pueden ser llevados a eventuales rondas de síntesis, ensayos bioquímicos y análisis estructural para su optimización. Los resultados de este proyecto de tesis están destinados a contribuir tanto en la generación de nuevos métodos computacionales como en la identificación de compuestos bioactivos contra el cáncer y muchas otras enfermedades aún prevalentes en el mundoDoctor en IngenieríaDoctorado263 hojasapplication/pdfengUniandesDoctorado en IngenieríaFacultad de Ingenieríainstname:Universidad de los Andesreponame:Repositorio Institucional SénecaDesign and discovery of new potential dual kinase back-pocket binders by fragmentation and virtual screening of natural productsTrabajo de grado - Doctoradoinfo:eu-repo/semantics/doctoralThesishttp://purl.org/coar/resource_type/c_db06http://purl.org/coar/version/c_970fb48d4fbd8a85Texthttp://purl.org/redcol/resource_type/TDCribado de alto rendimiento (Desarrollo de medicamentos) - InvestigacionesDesarrollo de medicamentos - InvestigcionesDinámica molecular - InvestigacionesBiomoléculas - InvestigacionesProteínas quinasas activadas por mitógenos - InvestigacionesDihidrofolato reductasa - InvestigacionesCáncer - Medicamentos - InvestigacionesIngenieríaPublicationORIGINALu833731.pdfapplication/pdf29109879https://repositorio.uniandes.edu.co/bitstreams/13ee2cae-bc61-4efd-9278-7083df79cb69/downloadc76b2222efd273f691c56ad8ec0a92beMD51TEXTu833731.pdf.txtu833731.pdf.txtExtracted texttext/plain397920https://repositorio.uniandes.edu.co/bitstreams/1712f4e7-45a6-463e-9194-da52e3439e7b/downloadb7c0bd4e4381d3cb975d1385f083d745MD54THUMBNAILu833731.pdf.jpgu833731.pdf.jpgIM Thumbnailimage/jpeg12338https://repositorio.uniandes.edu.co/bitstreams/4aee2b99-1b2d-480e-bb96-0c1254858aec/download36d5735e190dda15881f029cbb95bb41MD551992/48401oai:repositorio.uniandes.edu.co:1992/484012024-08-26 15:25:39.222https://repositorio.uniandes.edu.co/static/pdf/aceptacion_uso_es.pdfopen.accesshttps://repositorio.uniandes.edu.coRepositorio institucional Sénecaadminrepositorio@uniandes.edu.co |