Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking

Detalhes bibliográficos
Autor(a) principal: Karl, Ana Luiza Martins
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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spelling 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). 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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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