Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações do LNCC |
Texto Completo: | https://tede.lncc.br/handle/tede/310 |
Resumo: | With the improvement of computational power, computational techniques have been gaining increasing importance in pharmaceutical research, since they contribute to the reduction of time and cost in the planning of new drugs. The computational methodology known as molecular docking aims to predict binding modes and binding affinity of a small molecule (ligand) at the binding site of the biological target of interest (receptor). One of the great challenges of the area is the treatment of receptor flexibility, which – because it has many degrees of freedom – is difficult to be represented computationally. Thus, the receptor is usually treated as a rigid structure, as is currently done in the DockThor docking program, used in the present work. One of the simplest ways to handle receptor flexibility in docking methodology is through the soft-docking technique, which consists in softening the van der Waals potential, a common part of the evaluation function of docking programs. The DockThor program uses a function based on the MMFF94S force field as an evaluation function for the prediction of binding modes. Therefore, the present work consists in the development of a new version of the DockThor program that considers the flexibility of receptors through the soft docking technique. Experiments of redocking and crossdocking were performed in test sets with different characteristics to validate the strategy and to explore different degrees of softening. In general, the inclusion of the smoothed potential maintained or slightly improved results for the investigated sets. In crossdocking assays, the inclusion of the soft docking strategy demonstrated great potential for improvement in pose prediction, using single or multiple structures of the receptor in docking studies. Improvements in pose prediction due to the insertion of the soft docking approach were also able to yield slight improvements in binding affinity prediction. The inclusion of this new methodology makes the DockThor program even more robust for receptor-ligand interactions studies, contributing to the academic community and research groups in the field of drug design. |
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Dardenne, Laurent EmmanuelGuedes, Isabella AlvimCoordenação de Pós-Graduação e Aperfeiçoamento (COPGA)Nascimento, Alessandro S.Ramos, Ana CarolinaCustódio, Fábio Limahttp://lattes.cnpq.br/6591634765844259Karl, Ana Luiza Martins2023-03-02T17:58:42Z2019-02-25KARL, A. L. M. Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking. 2019. 97 f. Dissertação (Programa de Pós-Graduação em Modelagem Computacional) - Laboratório Nacional de Computação Científica, Petrópolis, 2019.https://tede.lncc.br/handle/tede/310With the improvement of computational power, computational techniques have been gaining increasing importance in pharmaceutical research, since they contribute to the reduction of time and cost in the planning of new drugs. The computational methodology known as molecular docking aims to predict binding modes and binding affinity of a small molecule (ligand) at the binding site of the biological target of interest (receptor). One of the great challenges of the area is the treatment of receptor flexibility, which – because it has many degrees of freedom – is difficult to be represented computationally. Thus, the receptor is usually treated as a rigid structure, as is currently done in the DockThor docking program, used in the present work. One of the simplest ways to handle receptor flexibility in docking methodology is through the soft-docking technique, which consists in softening the van der Waals potential, a common part of the evaluation function of docking programs. The DockThor program uses a function based on the MMFF94S force field as an evaluation function for the prediction of binding modes. Therefore, the present work consists in the development of a new version of the DockThor program that considers the flexibility of receptors through the soft docking technique. Experiments of redocking and crossdocking were performed in test sets with different characteristics to validate the strategy and to explore different degrees of softening. In general, the inclusion of the smoothed potential maintained or slightly improved results for the investigated sets. In crossdocking assays, the inclusion of the soft docking strategy demonstrated great potential for improvement in pose prediction, using single or multiple structures of the receptor in docking studies. Improvements in pose prediction due to the insertion of the soft docking approach were also able to yield slight improvements in binding affinity prediction. The inclusion of this new methodology makes the DockThor program even more robust for receptor-ligand interactions studies, contributing to the academic community and research groups in the field of drug design.Em paralelo ao ganho de poder computacional, técnicas computacionais vêm ganhando cada vez mais importância na pesquisa farmacêutica por contribuírem com a diminuição de tempo e custo no planejamento de novos fármacos. A metodologia computacional conhecida como docking molecular tem por objetivo prever modos e afinidade de ligação de uma pequena molécula (ligante) no sítio de ligação do alvo biológico de interesse (receptor). Um dos grandes desafios da área é o tratamento da flexibilidade do receptor que, por possuir muitos graus de liberdade, torna-se difícil de ser representado computacionalmente. Em decorrência disso, usualmente o receptor é tratado como uma estrutura rígida, como atualmente é feito no programa DockThor, utilizado neste trabalho. Uma das maneiras mais simples de tratar a flexibilidade do receptor na metodologia de docking é através da técnica de soft docking. A técnica consiste na suavização do potencial de van der Waals, o qual comumente faz parte da função de avaliação dos programas de docking. O programa DockThor utiliza uma função baseada no campo de força MMFF94S como função de avaliação para a predição de modos de ligação. Com isso, o presente trabalho consiste em um estudo sistemático da técnica de soft docking no programa DockThor. Experimentos de redocking e crossdocking foram realizados em conjuntos testes com diferentes características para validar a estratégia e explorar diferentes graus de suavização. De maneira geral, a inclusão da suavização manteve ou melhorou ligeiramente os resultados nos estudos de redocking, para os conjuntos testados. A inclusão do potencial suavizado foi capaz de acarretar até 4% de ganho médio para todos os conjuntos. Nos experimentos de cross- docking, a inclusão da suavização demonstrou grande potencial de melhora na previsão da pose, considerando uma ou múltiplas estruturas do receptor (ensemble docking). Além disso, as melhorias na previsão da pose foram também capazes de ocasionar ligeiras melhorias na previsão da afinidade. Assim, é possível dizer que a abordagem de soft docking é capaz de melhorar os resultados tanto da previsão da pose quanto da previsão da afinidade de ligação, utilizando o programa DockThor. A inclusão dessa metodologia torna o programa ainda mais robusto para estudos de interações receptor-ligante, contribuindo para comunidade acadêmica e grupos de pesquisa da área de planejamento de fármacos.Submitted by Parícia Vieira Silva (library@lncc.br) on 2023-03-02T17:58:16Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Ana Luiza_Dissertacao2019.pdf: 15926498 bytes, checksum: 22be58446bf14abf8fc59ae6161e46b3 (MD5)Approved for entry into archive by Parícia Vieira Silva (library@lncc.br) on 2023-03-02T17:58:29Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Ana Luiza_Dissertacao2019.pdf: 15926498 bytes, checksum: 22be58446bf14abf8fc59ae6161e46b3 (MD5)Made available in DSpace on 2023-03-02T17:58:42Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Ana Luiza_Dissertacao2019.pdf: 15926498 bytes, checksum: 22be58446bf14abf8fc59ae6161e46b3 (MD5) Previous issue date: 2019-02-25Conselho Nacional de Desenvolvimento Científico e Tecnológicoapplication/pdfhttp://tede-server.lncc.br:8080/retrieve/1164/Ana%20Luiza_Dissertacao2019.pdf.jpgporLaboratório Nacional de Computação CientíficaPrograma de Pós-Graduação em Modelagem ComputacionalLNCCBrasilCoordenação de Pós-Graduação e Aperfeiçoamento (COPGA)http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessFarmacologiaSimulação de acoplamento molecularDockThor (Programa de computador)CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAInclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Dockinginfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisreponame:Biblioteca Digital de Teses e Dissertações do LNCCinstname:Laboratório Nacional de Computação Científica (LNCC)instacron:LNCCLICENSElicense.txtlicense.txttext/plain; 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dc.title.por.fl_str_mv |
Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking |
title |
Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking |
spellingShingle |
Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking Karl, Ana Luiza Martins Farmacologia Simulação de acoplamento molecular DockThor (Programa de computador) CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking |
title_full |
Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking |
title_fullStr |
Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking |
title_full_unstemmed |
Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking |
title_sort |
Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking |
author |
Karl, Ana Luiza Martins |
author_facet |
Karl, Ana Luiza Martins |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Dardenne, Laurent Emmanuel |
dc.contributor.advisor-co1.fl_str_mv |
Guedes, Isabella Alvim |
dc.contributor.referee1.fl_str_mv |
Coordenação de Pós-Graduação e Aperfeiçoamento (COPGA) |
dc.contributor.referee2.fl_str_mv |
Nascimento, Alessandro S. |
dc.contributor.referee3.fl_str_mv |
Ramos, Ana Carolina |
dc.contributor.referee4.fl_str_mv |
Custódio, Fábio Lima |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/6591634765844259 |
dc.contributor.author.fl_str_mv |
Karl, Ana Luiza Martins |
contributor_str_mv |
Dardenne, Laurent Emmanuel Guedes, Isabella Alvim Coordenação de Pós-Graduação e Aperfeiçoamento (COPGA) Nascimento, Alessandro S. Ramos, Ana Carolina Custódio, Fábio Lima |
dc.subject.por.fl_str_mv |
Farmacologia Simulação de acoplamento molecular DockThor (Programa de computador) |
topic |
Farmacologia Simulação de acoplamento molecular DockThor (Programa de computador) CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
With the improvement of computational power, computational techniques have been gaining increasing importance in pharmaceutical research, since they contribute to the reduction of time and cost in the planning of new drugs. The computational methodology known as molecular docking aims to predict binding modes and binding affinity of a small molecule (ligand) at the binding site of the biological target of interest (receptor). One of the great challenges of the area is the treatment of receptor flexibility, which – because it has many degrees of freedom – is difficult to be represented computationally. Thus, the receptor is usually treated as a rigid structure, as is currently done in the DockThor docking program, used in the present work. One of the simplest ways to handle receptor flexibility in docking methodology is through the soft-docking technique, which consists in softening the van der Waals potential, a common part of the evaluation function of docking programs. The DockThor program uses a function based on the MMFF94S force field as an evaluation function for the prediction of binding modes. Therefore, the present work consists in the development of a new version of the DockThor program that considers the flexibility of receptors through the soft docking technique. Experiments of redocking and crossdocking were performed in test sets with different characteristics to validate the strategy and to explore different degrees of softening. In general, the inclusion of the smoothed potential maintained or slightly improved results for the investigated sets. In crossdocking assays, the inclusion of the soft docking strategy demonstrated great potential for improvement in pose prediction, using single or multiple structures of the receptor in docking studies. Improvements in pose prediction due to the insertion of the soft docking approach were also able to yield slight improvements in binding affinity prediction. The inclusion of this new methodology makes the DockThor program even more robust for receptor-ligand interactions studies, contributing to the academic community and research groups in the field of drug design. |
publishDate |
2019 |
dc.date.issued.fl_str_mv |
2019-02-25 |
dc.date.accessioned.fl_str_mv |
2023-03-02T17:58:42Z |
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dc.identifier.citation.fl_str_mv |
KARL, A. L. M. Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking. 2019. 97 f. Dissertação (Programa de Pós-Graduação em Modelagem Computacional) - Laboratório Nacional de Computação Científica, Petrópolis, 2019. |
dc.identifier.uri.fl_str_mv |
https://tede.lncc.br/handle/tede/310 |
identifier_str_mv |
KARL, A. L. M. Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking. 2019. 97 f. Dissertação (Programa de Pós-Graduação em Modelagem Computacional) - Laboratório Nacional de Computação Científica, Petrópolis, 2019. |
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