Evaluación in silico de péptidos derivados de la secuencia peptídica 8b-13 hacia el complejo FGF8b/FGFR

Propia

Autores:
Mendoza López, Angie Bibiana
Tipo de recurso:
Trabajo de grado de pregrado
Fecha de publicación:
2020
Institución:
Universidad Antonio Nariño
Repositorio:
Repositorio UAN
Idioma:
spa
OAI Identifier:
oai:repositorio.uan.edu.co:123456789/1495
Acceso en línea:
http://repositorio.uan.edu.co/handle/123456789/1495
Palabra clave:
Diseño de péptidos
Péptidos sintéticos
Factor de crecimiento de fibroblastos
Cáncer de próstata
Docking molecular
Peptide design
Synthetic peptides
Fibroblast growth factor
Prostate cancer
Docking molecular
Rights
openAccess
License
Attribution-NoDerivatives 4.0 International (CC BY-ND 4.0)
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oai_identifier_str oai:repositorio.uan.edu.co:123456789/1495
network_acronym_str UAntonioN2
network_name_str Repositorio UAN
repository_id_str
dc.title.es_ES.fl_str_mv Evaluación in silico de péptidos derivados de la secuencia peptídica 8b-13 hacia el complejo FGF8b/FGFR
title Evaluación in silico de péptidos derivados de la secuencia peptídica 8b-13 hacia el complejo FGF8b/FGFR
spellingShingle Evaluación in silico de péptidos derivados de la secuencia peptídica 8b-13 hacia el complejo FGF8b/FGFR
Diseño de péptidos
Péptidos sintéticos
Factor de crecimiento de fibroblastos
Cáncer de próstata
Docking molecular
Peptide design
Synthetic peptides
Fibroblast growth factor
Prostate cancer
Docking molecular
title_short Evaluación in silico de péptidos derivados de la secuencia peptídica 8b-13 hacia el complejo FGF8b/FGFR
title_full Evaluación in silico de péptidos derivados de la secuencia peptídica 8b-13 hacia el complejo FGF8b/FGFR
title_fullStr Evaluación in silico de péptidos derivados de la secuencia peptídica 8b-13 hacia el complejo FGF8b/FGFR
title_full_unstemmed Evaluación in silico de péptidos derivados de la secuencia peptídica 8b-13 hacia el complejo FGF8b/FGFR
title_sort Evaluación in silico de péptidos derivados de la secuencia peptídica 8b-13 hacia el complejo FGF8b/FGFR
dc.creator.fl_str_mv Mendoza López, Angie Bibiana
dc.contributor.advisor.spa.fl_str_mv García Contreras, German Antonio
dc.contributor.author.spa.fl_str_mv Mendoza López, Angie Bibiana
dc.subject.es_ES.fl_str_mv Diseño de péptidos
Péptidos sintéticos
Factor de crecimiento de fibroblastos
Cáncer de próstata
Docking molecular
topic Diseño de péptidos
Péptidos sintéticos
Factor de crecimiento de fibroblastos
Cáncer de próstata
Docking molecular
Peptide design
Synthetic peptides
Fibroblast growth factor
Prostate cancer
Docking molecular
dc.subject.keyword.es_ES.fl_str_mv Peptide design
Synthetic peptides
Fibroblast growth factor
Prostate cancer
Docking molecular
description Propia
publishDate 2020
dc.date.issued.spa.fl_str_mv 2020-11-18
dc.date.accessioned.none.fl_str_mv 2021-02-18T18:44:08Z
dc.date.available.none.fl_str_mv 2021-02-18T18:44:08Z
dc.type.spa.fl_str_mv Trabajo de grado (Pregrado y/o Especialización)
dc.type.coar.spa.fl_str_mv http://purl.org/coar/resource_type/c_7a1f
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format http://purl.org/coar/resource_type/c_7a1f
dc.identifier.uri.none.fl_str_mv http://repositorio.uan.edu.co/handle/123456789/1495
dc.identifier.bibliographicCitation.spa.fl_str_mv Siegel, R. L., Miller, K. D., & Jemal, A. (2019). Cancer statistics, 2019. CA: a cancer journal for clinicians, 69(1), 7-34.
Acuña, L. (11 de Julio de 2019). Cuenta de Alto Costo. Obtenido de https://www.cuentadealtocosto.org/site/images/Reporte_Especial_Dia_mundial_del_cancer_de_prostata_2019.pdf.
Coughlin, S. S. (2019). A Review of Social Determinants of Prostate Cancer Risk,Stage, and Survival. Prostate International.
Bidwell III, G. L., & Raucher, D. (2009). Therapeutic peptides for cancer therapy. Part I–peptide inhibitors of signal transduction cascades. Expert opinion on drug delivery,6(10), 1033-1047.
Li, T., Luo, W., He, D., Wang, R., Huang, Y., Zeng, X., ... & Li, X. (2013). A short peptide derived from the gN helix domain of FGF8b suppresses the growth of human prostate cancer cells. Cancer letters, 339(2), 226-236.
Valta, M. P., Tuomela, J., Bjartell, A., Valve, E., Väänänen, H. K., & Härkönen, P.(2008). FGF‐8 is involved in bone metastasis of prostate cancer. International journal of cancer, 123(1), 22-31.
Gnanapragasam, V. J., Robinson, M. C., Marsh, C., Robson, C. N., Hamdy, F. C., & Leung, H. Y. (2003). FGF8 isoform b expression in human prostate cancer. British journal of cancer, 88(9), 1432-1438.
Dorkin, T. J., Robinson, M. C., Marsh, C., Bjartell, A., Neal, D. E., & Leung, H. Y. (1999). FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease. Oncogene, 18(17),2755.
Drake, J. M., Graham, N. A., Lee, J. K., Stoyanova, T., Faltermeier, C. M., Sud, S., ... & Witte, O. N. (2013). Metastatic castration-resistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets.Proceedings of the National Academy of Sciences, 110(49), E4762-E4769.
Gdowski, A. S., Ranjan, A., & Vishwanatha, J. K. (2017). Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials. Journal of Experimental & Clinical Cancer Research, 36(1), 108.
Liu, H., Lin, X., Huang, T., Song, L., Zhu, C., Ma, H., ... & Huang, Y. (2018). A short peptide reverses the aggressive phenotype of prostate cancer cells. European journal of pharmacology, 838, 129-137.
Rentzsch, R., & Renard, B. Y. (2015). Docking small peptides remains a great challenge: an assessment using AutoDock Vina. Briefings in Bioinformatics, 16(6), 1045-1056.
Shen Y, Maupetit J, Derreumaux P, Tufféry P. Improved PEP-FOLD approach for peptide and miniprotein structure prediction J. Chem. Theor. Comput. 2014; 10:4745-4758
Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of computational chemistry, 30(16), 2785-2791.
O. Trott, A. J. Olson, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading, Journal of Computational Chemistry 31 (2010) 455-46. DOI 10.1002/jcc.21334.
Seeliger, D., & de Groot, B. L. (2010). Ligand docking and binding site analysis with PyMOL and Autodock/Vina. Journal of computer-aided molecular design, 24(5), 417-422.
Raschka, S. (2014). Molecular docking, estimating free energies of binding, andAutoDock's semi‐empirical force field.
BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego: Dassault Systèmes, 2016.
Chang, K. Y., & Yang, J. R. (2013). Analysis and prediction of highly effective antiviral peptides based on random forests. PloS one, 8(8), e70166.
url http://repositorio.uan.edu.co/handle/123456789/1495
identifier_str_mv Siegel, R. L., Miller, K. D., & Jemal, A. (2019). Cancer statistics, 2019. CA: a cancer journal for clinicians, 69(1), 7-34.
Acuña, L. (11 de Julio de 2019). Cuenta de Alto Costo. Obtenido de https://www.cuentadealtocosto.org/site/images/Reporte_Especial_Dia_mundial_del_cancer_de_prostata_2019.pdf.
Coughlin, S. S. (2019). A Review of Social Determinants of Prostate Cancer Risk,Stage, and Survival. Prostate International.
Bidwell III, G. L., & Raucher, D. (2009). Therapeutic peptides for cancer therapy. Part I–peptide inhibitors of signal transduction cascades. Expert opinion on drug delivery,6(10), 1033-1047.
Li, T., Luo, W., He, D., Wang, R., Huang, Y., Zeng, X., ... & Li, X. (2013). A short peptide derived from the gN helix domain of FGF8b suppresses the growth of human prostate cancer cells. Cancer letters, 339(2), 226-236.
Valta, M. P., Tuomela, J., Bjartell, A., Valve, E., Väänänen, H. K., & Härkönen, P.(2008). FGF‐8 is involved in bone metastasis of prostate cancer. International journal of cancer, 123(1), 22-31.
Gnanapragasam, V. J., Robinson, M. C., Marsh, C., Robson, C. N., Hamdy, F. C., & Leung, H. Y. (2003). FGF8 isoform b expression in human prostate cancer. British journal of cancer, 88(9), 1432-1438.
Dorkin, T. J., Robinson, M. C., Marsh, C., Bjartell, A., Neal, D. E., & Leung, H. Y. (1999). FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease. Oncogene, 18(17),2755.
Drake, J. M., Graham, N. A., Lee, J. K., Stoyanova, T., Faltermeier, C. M., Sud, S., ... & Witte, O. N. (2013). Metastatic castration-resistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets.Proceedings of the National Academy of Sciences, 110(49), E4762-E4769.
Gdowski, A. S., Ranjan, A., & Vishwanatha, J. K. (2017). Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials. Journal of Experimental & Clinical Cancer Research, 36(1), 108.
Liu, H., Lin, X., Huang, T., Song, L., Zhu, C., Ma, H., ... & Huang, Y. (2018). A short peptide reverses the aggressive phenotype of prostate cancer cells. European journal of pharmacology, 838, 129-137.
Rentzsch, R., & Renard, B. Y. (2015). Docking small peptides remains a great challenge: an assessment using AutoDock Vina. Briefings in Bioinformatics, 16(6), 1045-1056.
Shen Y, Maupetit J, Derreumaux P, Tufféry P. Improved PEP-FOLD approach for peptide and miniprotein structure prediction J. Chem. Theor. Comput. 2014; 10:4745-4758
Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of computational chemistry, 30(16), 2785-2791.
O. Trott, A. J. Olson, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading, Journal of Computational Chemistry 31 (2010) 455-46. DOI 10.1002/jcc.21334.
Seeliger, D., & de Groot, B. L. (2010). Ligand docking and binding site analysis with PyMOL and Autodock/Vina. Journal of computer-aided molecular design, 24(5), 417-422.
Raschka, S. (2014). Molecular docking, estimating free energies of binding, andAutoDock's semi‐empirical force field.
BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego: Dassault Systèmes, 2016.
Chang, K. Y., & Yang, J. R. (2013). Analysis and prediction of highly effective antiviral peptides based on random forests. PloS one, 8(8), e70166.
dc.language.iso.spa.fl_str_mv spa
language spa
dc.rights.none.fl_str_mv Acceso abierto
dc.rights.license.spa.fl_str_mv Attribution-NoDerivatives 4.0 International (CC BY-ND 4.0)
dc.rights.uri.spa.fl_str_mv https://creativecommons.org/licenses/by-nd/4.0/
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Acceso abierto
https://creativecommons.org/licenses/by-nd/4.0/
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.publisher.spa.fl_str_mv Universidad Antonio Nariño
dc.publisher.program.spa.fl_str_mv Bioquímica
dc.publisher.faculty.spa.fl_str_mv Facultad de Ciencias
dc.publisher.campus.spa.fl_str_mv Bogotá - Circunvalar
institution Universidad Antonio Nariño
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spelling Attribution-NoDerivatives 4.0 International (CC BY-ND 4.0)Acceso abiertohttps://creativecommons.org/licenses/by-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2García Contreras, German AntonioMendoza López, Angie Bibianahttps://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=00017880121022430108802285982021-02-18T18:44:08Z2021-02-18T18:44:08Z2020-11-18http://repositorio.uan.edu.co/handle/123456789/1495Siegel, R. L., Miller, K. D., & Jemal, A. (2019). Cancer statistics, 2019. CA: a cancer journal for clinicians, 69(1), 7-34.Acuña, L. (11 de Julio de 2019). Cuenta de Alto Costo. Obtenido de https://www.cuentadealtocosto.org/site/images/Reporte_Especial_Dia_mundial_del_cancer_de_prostata_2019.pdf.Coughlin, S. S. (2019). A Review of Social Determinants of Prostate Cancer Risk,Stage, and Survival. Prostate International.Bidwell III, G. L., & Raucher, D. (2009). Therapeutic peptides for cancer therapy. Part I–peptide inhibitors of signal transduction cascades. Expert opinion on drug delivery,6(10), 1033-1047.Li, T., Luo, W., He, D., Wang, R., Huang, Y., Zeng, X., ... & Li, X. (2013). A short peptide derived from the gN helix domain of FGF8b suppresses the growth of human prostate cancer cells. Cancer letters, 339(2), 226-236.Valta, M. P., Tuomela, J., Bjartell, A., Valve, E., Väänänen, H. K., & Härkönen, P.(2008). FGF‐8 is involved in bone metastasis of prostate cancer. International journal of cancer, 123(1), 22-31.Gnanapragasam, V. J., Robinson, M. C., Marsh, C., Robson, C. N., Hamdy, F. C., & Leung, H. Y. (2003). FGF8 isoform b expression in human prostate cancer. British journal of cancer, 88(9), 1432-1438.Dorkin, T. J., Robinson, M. C., Marsh, C., Bjartell, A., Neal, D. E., & Leung, H. Y. (1999). FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease. Oncogene, 18(17),2755.Drake, J. M., Graham, N. A., Lee, J. K., Stoyanova, T., Faltermeier, C. M., Sud, S., ... & Witte, O. N. (2013). Metastatic castration-resistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets.Proceedings of the National Academy of Sciences, 110(49), E4762-E4769.Gdowski, A. S., Ranjan, A., & Vishwanatha, J. K. (2017). Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials. Journal of Experimental & Clinical Cancer Research, 36(1), 108.Liu, H., Lin, X., Huang, T., Song, L., Zhu, C., Ma, H., ... & Huang, Y. (2018). A short peptide reverses the aggressive phenotype of prostate cancer cells. European journal of pharmacology, 838, 129-137.Rentzsch, R., & Renard, B. Y. (2015). Docking small peptides remains a great challenge: an assessment using AutoDock Vina. Briefings in Bioinformatics, 16(6), 1045-1056.Shen Y, Maupetit J, Derreumaux P, Tufféry P. Improved PEP-FOLD approach for peptide and miniprotein structure prediction J. Chem. Theor. Comput. 2014; 10:4745-4758Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of computational chemistry, 30(16), 2785-2791.O. Trott, A. J. Olson, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading, Journal of Computational Chemistry 31 (2010) 455-46. DOI 10.1002/jcc.21334.Seeliger, D., & de Groot, B. L. (2010). Ligand docking and binding site analysis with PyMOL and Autodock/Vina. Journal of computer-aided molecular design, 24(5), 417-422.Raschka, S. (2014). Molecular docking, estimating free energies of binding, andAutoDock's semi‐empirical force field.BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego: Dassault Systèmes, 2016.Chang, K. Y., & Yang, J. R. (2013). Analysis and prediction of highly effective antiviral peptides based on random forests. PloS one, 8(8), e70166.PropiaProstate cancer is the malignant growth of the prostate gland; It occurs when the cells of the prostate mutate and multiply uncontrollably. Fibroblast growth factor 8b (FGF8b) is expressed in a large percentage of patients with prostate cancer and plays a key role in the appearance and development of this cancer. Various studies have shown that the synthetic peptide 8b-13, derived from the gN helix domain of FGF8b, blocks the interaction of FGF8b with the fibroblast growth factor receptor (FGFR), inhibiting the proliferation of prostate cancer cell lines . To identify the affinity towards the FGF8b/FGFR complex of peptides derived from 8b-13, a peptide library was proposed by making cuts at the amino and carboxyl termini of the 8b-13 sequence. The affinity towards the FGF8b/FGFR complex was evaluated and the key amino acids for the interaction were identified by means of molecular docking tests, using the algorithm of AutoDock Vina, Chimera and Discovery Studio. The results propose viable peptides to be candidates in experimental trials that could demonstrate the inhibition of cancer cell proliferation, developing tools for the possible treatment of prostate cancer.El cáncer de próstata es el crecimiento maligno de la glándula prostática; se produce cuando las células de la próstata mutan y se multiplican descontroladamente. El factor de crecimiento de fibroblastos 8b (FGF8b) se encuentra expresado en un gran porcentaje de pacientes con cáncer de próstata y desempeña un papel clave en la aparición y desarrollo de este cáncer. Diversos estudios han demostrado que el péptido sintético denominado 8b13, procedente del dominio de hélice gN del FGF8b, bloquea la interacción del FGF8b con el receptor de factor de crecimiento de fibroblastos (FGFR), inhibiendo la proliferación de líneas celulares del cáncer de próstata. Para identificar la afinidad hacía el complejo FGF8b/FGFR de péptidos derivados del 8b 13, se propuso una librería peptídica realizando cortes en los extremos amino y carboxilo terminal de la secuencia del 8b-13. Se evaluó la afinidad hacía el complejo FGF8b/FGFR y se identificó los aminoácidos claves para la interacción por medio de pruebas de docking molecular, utilizando el algoritmo de AutoDock Vina, Chimera y Discovery Studio. Los resultados proponen péptidos viables para ser candidatos en ensayos experimentales que podrían demostrar la inhibición de la proliferación de células cancerígenas, desarrollando herramientas para el posible tratamiento del cáncer de próstata.OtroBioquímico(a)PregradoNingunaPresencialspaUniversidad Antonio NariñoBioquímicaFacultad de CienciasBogotá - CircunvalarDiseño de péptidosPéptidos sintéticosFactor de crecimiento de fibroblastosCáncer de próstataDocking molecularPeptide designSynthetic peptidesFibroblast growth factorProstate cancerDocking molecularEvaluación in silico de péptidos derivados de la secuencia peptídica 8b-13 hacia el complejo FGF8b/FGFRTrabajo de grado (Pregrado y/o Especialización)http://purl.org/coar/resource_type/c_7a1fhttp://purl.org/coar/version/c_970fb48d4fbd8a85ORIGINAL2020AngieBibianaMendozaLopez.pdf2020AngieBibianaMendozaLopez.pdfTrabajo de gradoapplication/pdf1758858https://repositorio.uan.edu.co/bitstreams/58d72f0a-10c8-44cf-9909-b40554e19e13/download67f924cb799c54d3b8eaa7a853f3847bMD512020AutorizaciondeAutores.pdf2020AutorizaciondeAutores.pdfAutorización autoresapplication/pdf209765https://repositorio.uan.edu.co/bitstreams/5f3a5e9b-5029-495e-873a-8f590c46dc02/download9253a8d7bda16574d2b8d4278aca8c92MD52CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8805https://repositorio.uan.edu.co/bitstreams/7ea3fb24-07e8-40d5-9304-5b379eb9e5c0/download5812a2eee99d5585fc0c26f0033099bbMD53LICENSElicense.txtlicense.txttext/plain; charset=utf-82710https://repositorio.uan.edu.co/bitstreams/12983aeb-cc5b-458d-9753-4efdda112998/download2e388663398085f69421c9e4c5fcf235MD54123456789/1495oai:repositorio.uan.edu.co:123456789/14952024-10-09 22:58:24.992https://creativecommons.org/licenses/by-nd/4.0/Acceso abiertoopen.accesshttps://repositorio.uan.edu.coRepositorio Institucional UANalertas.repositorio@uan.edu.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