Desarrollo y síntesis de un análogo de los quimioterapéuticos inhibidores de la topoisomerasa I, por metodologías de cribado virtual basadas en cambios bioisostéricos y QSAR

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dc.contributor.advisorGuevara Pulido, James Oswaldo
dc.contributor.authorRodriguez Velandia , Sara Daniela
dc.contributor.authorMoreno Tranchita, Juan Pablo
dc.date.accessioned2024-05-16T02:45:06Z
dc.date.available2024-05-16T02:45:06Z
dc.date.issued2024-04-30
dc.description.abstractLa incidencia del cáncer colorrectal ha aumentado considerablemente, convirtiéndolo en un problema de salud pública global. Su complejidad genera diagnósticos tardíos y tratamientos con baja eficacia, lo que conlleva a una alta carga de efectos adversos para los pacientes. En respuesta a esta problemática, se diseñó y sintetizó un nuevo análogo inhibidor de la ADN topoisomerasa 1. Este proceso se basó en el diseño racional de fármacos, utilizando cambios bioisostéricos y metodologías de SBVS y LBVS con machine learning. Se desarrollaron tres modelos predictivos validados en líneas celulares de cáncer colorrectal HCT-116, HCT-8 y HT-29. Entre 59 análogos diseñados, el A12 se destaca por sus mejoras en comparación con Irinotecan, Topotecan y Doxorubicina. A12 presenta una buena afinidad por la ADN topoisomerasa 1 (6,8 Kcal/mol) y un menor IC50 (0,23 μM en HCT- 116). Además, presenta mejoras farmacocinéticas (PPB 89,6%, Log P 3,22) y un perfil de toxicidad similar a los fármacos comerciales. El desarrollo del análogo A12 representa un avance significativo en la búsqueda de nuevas opciones terapéuticas para el cáncer colorrectal. Sus propiedades farmacológicas y de seguridad lo convierten en un candidato prometedor para futuras investigaciones preclínicas
dc.description.abstractenglishThe incidence of colorectal cancer has significantly increased, turning it into a global public health issue. Its complexity leads to late diagnoses and treatments with low efficacy, resulting in a high burden of adverse effects for patients. In response to this challenge, a new analog inhibitor of DNA topoisomerase 1 was designed and synthesized. This process was based on rational drug design, utilizing bioisosteric changes and SBVS and LBVS methodologies with machine learning. Three predictive models were developed and validated in colorectal cancer cell lines HCT-116, HCT-8, and HT-29. Among 59 designed analogs, A12 stands out for its improvements compared to Irinotecan, Topotecan, and Doxorubicin. A12 shows good affinity for DNA topoisomerase 1 (6.8 Kcal/mol) and a lower IC50 (0.23 μM in HCT-116). Additionally, it exhibits improved pharmacokinetics (PPB 89.6%, Log P 3.22) and a toxicity profile similar to commercial drugs. The development of the A12 analog represents a significant advancement in the search for new therapeutic options for colorectal cancer. Its pharmacological properties and safety profile make it a promising candidate for future preclinical research.
dc.description.degreelevelPregradospa
dc.description.degreelevelQuímico Farmacéuticospa
dc.format.mimetypeapplication/pdf
dc.identifier.instnameUniversidad El Bosquespa
dc.identifier.reponamereponame:Repositorio Institucional Universidad El Bosquespa
dc.identifier.repourlrepourl:https://repositorio.unbosque.edu.co
dc.identifier.urihttps://hdl.handle.net/20.500.12495/12133
dc.language.isoes
dc.publisher.facultyFacultad de Cienciasspa
dc.publisher.grantorUniversidad El Bosquespa
dc.publisher.programQuímica Farmacéuticaspa
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dc.rights.accessrightsinfo:eu-repo/semantics/closedAccess
dc.rights.accessrightshttp://purl.org/coar/access_right/c_14cb
dc.rights.localAcceso cerradospa
dc.subjectCáncer colorrectal
dc.subjectAND topoisomerasa 1
dc.subjectMachine learning
dc.subjectQSAR
dc.subjectFarmacocinética
dc.subjectFarmacodinamia
dc.subject.ddc615.19
dc.subject.keywordsColorectal cancer
dc.subject.keywordsDNA topoisomerase 1
dc.subject.keywordsMachine learning
dc.subject.keywordsQSAR
dc.subject.keywordsPharmacokinetics
dc.subject.keywordsPharmacodynamics
dc.titleDesarrollo y síntesis de un análogo de los quimioterapéuticos inhibidores de la topoisomerasa I, por metodologías de cribado virtual basadas en cambios bioisostéricos y QSAR
dc.title.translatedDevelopment and synthesis of an analog of the chemotherapeutic topoisomerase I inhibitors, using virtual screening methodologies based on bioisosteric changes and QSAR.
dc.type.coarhttps://purl.org/coar/resource_type/c_7a1f
dc.type.coarversionhttps://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.driverinfo:eu-repo/semantics/bachelorThesis
dc.type.hasversioninfo:eu-repo/semantics/acceptedVersion
dc.type.localTesis/Trabajo de grado - Monografía - Pregrado

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