Computational Study of the interaction of acridine derivatives with DNA
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10773/29324 |
Resumo: | DNA is a significant target for the treatment of many diseases, including cancer. DNA intercalation is the process by which small molecules containing planar aromatic or heteroaromatic systems, are inserted between the adjacent DNA base pairs. Intercalation leads to many conformational changes in DNA with concomitant interference with its biological functions. Experimental procedures to evaluate the binding mode between drug candidates and DNA involve risks and are time and money consuming. These drawbacks can be avoided with the use of computer-aided techniques. Acridines and its derivatives have been showing great potential in developing new antitumoral drugs mainly due to their DNA-intercalative properties, which are enhanced by their acceptor/donor nitrogen atoms and planar structure. The antiproliferative properties may be altered upon grafting different ligands into the acridine ring, making them useful moieties for the development of target-based drug discovery. Molecular docking techniques allows the prediction of the most probable orientation of drug candidates against their targets and the corresponding binding affinities. The studies can be complemented with results from molecular dynamics (MD) simulations for further validation under more realistic conditions. Therefore, molecular docking and MD simulations may be employed to better understand the relationship between different substituents and the affinities of the resulting compounds to DNA, hence, to anticipate their antitumoral potential. In this work, computational tools, docking and molecular dynamics, were used to study the interaction of three acridine derivatives (compounds 5a-c) with five different DNA models. Through the results it was possible to infer which modes of interaction with DNA were possible for each compound: threading intercalation for compound 5a, minor groove and threading intercalation for compound 5b, and minor groove or classic intercalation for compound 5c. |
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Computational Study of the interaction of acridine derivatives with DNACancerDNAIntercalationAcridine derivativesMolecular dockingDNA is a significant target for the treatment of many diseases, including cancer. DNA intercalation is the process by which small molecules containing planar aromatic or heteroaromatic systems, are inserted between the adjacent DNA base pairs. Intercalation leads to many conformational changes in DNA with concomitant interference with its biological functions. Experimental procedures to evaluate the binding mode between drug candidates and DNA involve risks and are time and money consuming. These drawbacks can be avoided with the use of computer-aided techniques. Acridines and its derivatives have been showing great potential in developing new antitumoral drugs mainly due to their DNA-intercalative properties, which are enhanced by their acceptor/donor nitrogen atoms and planar structure. The antiproliferative properties may be altered upon grafting different ligands into the acridine ring, making them useful moieties for the development of target-based drug discovery. Molecular docking techniques allows the prediction of the most probable orientation of drug candidates against their targets and the corresponding binding affinities. The studies can be complemented with results from molecular dynamics (MD) simulations for further validation under more realistic conditions. Therefore, molecular docking and MD simulations may be employed to better understand the relationship between different substituents and the affinities of the resulting compounds to DNA, hence, to anticipate their antitumoral potential. In this work, computational tools, docking and molecular dynamics, were used to study the interaction of three acridine derivatives (compounds 5a-c) with five different DNA models. Through the results it was possible to infer which modes of interaction with DNA were possible for each compound: threading intercalation for compound 5a, minor groove and threading intercalation for compound 5b, and minor groove or classic intercalation for compound 5c.O ADN é um alvo crucial no tratamento de muitas doenças, incluindo o cancro. A intercalação do ADN é o processo através do qual pequenas moléculas contendo sistemas aromáticos ou heteroaromáticos planares, são inseridas entre os pares de bases adjacentes. A intercalação resulta em múltiplas alterações conformacionais na DNA que interferem, consequentemente, com as suas funções biológicas. Procedimentos experimentais para avaliar o modo de ligação entre candidatos a fármacos e o DNA envolvem riscos, e consomem tempo e dinheiro. Estas desvantagens podem ser evitadas com o uso de técnicas computacionais. As acridinas e os seus derivados têm demonstrado um grande potencial no desenvolvimento de novas drogas antitumorais, principalmente devido às suas propriedades intercaladoras do DNA, que são potenciadas pelos seus átomos aceitadores/dadores de nitrogênio e pela sua estrutura planar. As propriedades antiproliferativas das acridinas podem ser alteradas com a substituição de diferentes ligandos no seu anel, tornando-o o núcleo destes compostos um alvo de grande interesse no desenvolvimento e descoberta de novos fármacos. As técnicas de acoplamento molecular permitem a previsão da orientação mais provável de candidatos a fármacos face aos seus alvos e, para além disso, das respetivas afinidades de ligação. Estes estudos podem ser complementados com resultados de simulações de dinâmica molecular (MD) para posterior validação sob condições mais realistas. Desta forma, o acoplamento molecular e as simulações MD podem ser utilizados para uma melhor perceção da relação entre diferentes substituintes e as afinidades dos compostos resultantes com o DNA, ou seja, para antecipar os seu potenciais antitumorais. Neste trabalho foram utilizadas ferramentas computacionais, acoplamento e dinâmica molecular, para estudar a interação de três derivados de acridina com cinco modelos de ADN diferentes. Através dos resultados foi possível inferir quais os possíveis modos de interação com o DNA para cada composto: intercalação threading para o composto 5a, intercalação threading ou interação com o minor groove para o composto 5b, e intercalação clássica ou interação com o minor groove para o composto 5c.2022-08-06T00:00:00Z2020-07-27T00:00:00Z2020-07-27info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10773/29324engPedro, Maria Beatriz Pinto Lopesinfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-02-22T11:56:45Zoai:ria.ua.pt:10773/29324Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:01:42.145045Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Computational Study of the interaction of acridine derivatives with DNA |
title |
Computational Study of the interaction of acridine derivatives with DNA |
spellingShingle |
Computational Study of the interaction of acridine derivatives with DNA Pedro, Maria Beatriz Pinto Lopes Cancer DNA Intercalation Acridine derivatives Molecular docking |
title_short |
Computational Study of the interaction of acridine derivatives with DNA |
title_full |
Computational Study of the interaction of acridine derivatives with DNA |
title_fullStr |
Computational Study of the interaction of acridine derivatives with DNA |
title_full_unstemmed |
Computational Study of the interaction of acridine derivatives with DNA |
title_sort |
Computational Study of the interaction of acridine derivatives with DNA |
author |
Pedro, Maria Beatriz Pinto Lopes |
author_facet |
Pedro, Maria Beatriz Pinto Lopes |
author_role |
author |
dc.contributor.author.fl_str_mv |
Pedro, Maria Beatriz Pinto Lopes |
dc.subject.por.fl_str_mv |
Cancer DNA Intercalation Acridine derivatives Molecular docking |
topic |
Cancer DNA Intercalation Acridine derivatives Molecular docking |
description |
DNA is a significant target for the treatment of many diseases, including cancer. DNA intercalation is the process by which small molecules containing planar aromatic or heteroaromatic systems, are inserted between the adjacent DNA base pairs. Intercalation leads to many conformational changes in DNA with concomitant interference with its biological functions. Experimental procedures to evaluate the binding mode between drug candidates and DNA involve risks and are time and money consuming. These drawbacks can be avoided with the use of computer-aided techniques. Acridines and its derivatives have been showing great potential in developing new antitumoral drugs mainly due to their DNA-intercalative properties, which are enhanced by their acceptor/donor nitrogen atoms and planar structure. The antiproliferative properties may be altered upon grafting different ligands into the acridine ring, making them useful moieties for the development of target-based drug discovery. Molecular docking techniques allows the prediction of the most probable orientation of drug candidates against their targets and the corresponding binding affinities. The studies can be complemented with results from molecular dynamics (MD) simulations for further validation under more realistic conditions. Therefore, molecular docking and MD simulations may be employed to better understand the relationship between different substituents and the affinities of the resulting compounds to DNA, hence, to anticipate their antitumoral potential. In this work, computational tools, docking and molecular dynamics, were used to study the interaction of three acridine derivatives (compounds 5a-c) with five different DNA models. Through the results it was possible to infer which modes of interaction with DNA were possible for each compound: threading intercalation for compound 5a, minor groove and threading intercalation for compound 5b, and minor groove or classic intercalation for compound 5c. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-07-27T00:00:00Z 2020-07-27 2022-08-06T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10773/29324 |
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http://hdl.handle.net/10773/29324 |
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eng |
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eng |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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