Analysis of α4 β1integrin specific antagonists binding modes: structural insights by molecular docking, molecular dynamics and linear interaction energy method for free energy calculations
Autor(a) principal: | |
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Data de Publicação: | 2010 |
Outros Autores: | , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Journal of the Brazilian Chemical Society (Online) |
Texto Completo: | http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532010000300022 |
Resumo: | The VLA-4 antigen (α4β1 integrin) is involved in the pathophysiology of a variety of diseases including asthma, multiple sclerosis, rheumatoid arthritis and diabetes. The ligand selectivity toward this integrin remains a difficult problem, mainly due to the fact that 3D structures of most integrins are still unknown. We initially built a 3D computational model of the α4β1 ligand binding site, taking the crystal structure of the integrin αVβ3 as template. Then, we performed a computational study on a set of seven α4β1 antagonists, evaluating the binding modes of 4-[N'-(2-methylphenyl)ureido]phenylacetyl and derivatives by molecular docking. Molecular dynamics simulations were used to improve the receptor-ligand energy landscape exploration by the docking algorithm. The compounds were systematically arranged in two main binding modes, and in all cases, pointed out that these antagonists preferably bind to the α4β1 integrin active site in an extended conformation that resembles the one in solution. LIE (linear interaction energy) calculations also confirmed this statement given that the most prevailing binding mode is also the energetically most favored one. This study benefits the comprehension of the mechanism of this family of antagonists and may provide useful information for rational drug design. |
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Analysis of α4 β1integrin specific antagonists binding modes: structural insights by molecular docking, molecular dynamics and linear interaction energy method for free energy calculationsinflammationintegrinsVLA-4dockingmolecular dynamicsThe VLA-4 antigen (α4β1 integrin) is involved in the pathophysiology of a variety of diseases including asthma, multiple sclerosis, rheumatoid arthritis and diabetes. The ligand selectivity toward this integrin remains a difficult problem, mainly due to the fact that 3D structures of most integrins are still unknown. We initially built a 3D computational model of the α4β1 ligand binding site, taking the crystal structure of the integrin αVβ3 as template. Then, we performed a computational study on a set of seven α4β1 antagonists, evaluating the binding modes of 4-[N'-(2-methylphenyl)ureido]phenylacetyl and derivatives by molecular docking. Molecular dynamics simulations were used to improve the receptor-ligand energy landscape exploration by the docking algorithm. The compounds were systematically arranged in two main binding modes, and in all cases, pointed out that these antagonists preferably bind to the α4β1 integrin active site in an extended conformation that resembles the one in solution. LIE (linear interaction energy) calculations also confirmed this statement given that the most prevailing binding mode is also the energetically most favored one. This study benefits the comprehension of the mechanism of this family of antagonists and may provide useful information for rational drug design.Sociedade Brasileira de Química2010-01-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersiontext/htmlhttp://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532010000300022Journal of the Brazilian Chemical Society v.21 n.3 2010reponame:Journal of the Brazilian Chemical Society (Online)instname:Sociedade Brasileira de Química (SBQ)instacron:SBQ10.1590/S0103-50532010000300022info:eu-repo/semantics/openAccessSilva,João Hermínio Martins daDardenne,Laurent EmmanuelSavino,WilsonCaffarena,Ernesto Rauleng2010-04-30T00:00:00Zoai:scielo:S0103-50532010000300022Revistahttp://jbcs.sbq.org.brONGhttps://old.scielo.br/oai/scielo-oai.php||office@jbcs.sbq.org.br1678-47900103-5053opendoar:2010-04-30T00:00Journal of the Brazilian Chemical Society (Online) - Sociedade Brasileira de Química (SBQ)false |
dc.title.none.fl_str_mv |
Analysis of α4 β1integrin specific antagonists binding modes: structural insights by molecular docking, molecular dynamics and linear interaction energy method for free energy calculations |
title |
Analysis of α4 β1integrin specific antagonists binding modes: structural insights by molecular docking, molecular dynamics and linear interaction energy method for free energy calculations |
spellingShingle |
Analysis of α4 β1integrin specific antagonists binding modes: structural insights by molecular docking, molecular dynamics and linear interaction energy method for free energy calculations Silva,João Hermínio Martins da inflammation integrins VLA-4 docking molecular dynamics |
title_short |
Analysis of α4 β1integrin specific antagonists binding modes: structural insights by molecular docking, molecular dynamics and linear interaction energy method for free energy calculations |
title_full |
Analysis of α4 β1integrin specific antagonists binding modes: structural insights by molecular docking, molecular dynamics and linear interaction energy method for free energy calculations |
title_fullStr |
Analysis of α4 β1integrin specific antagonists binding modes: structural insights by molecular docking, molecular dynamics and linear interaction energy method for free energy calculations |
title_full_unstemmed |
Analysis of α4 β1integrin specific antagonists binding modes: structural insights by molecular docking, molecular dynamics and linear interaction energy method for free energy calculations |
title_sort |
Analysis of α4 β1integrin specific antagonists binding modes: structural insights by molecular docking, molecular dynamics and linear interaction energy method for free energy calculations |
author |
Silva,João Hermínio Martins da |
author_facet |
Silva,João Hermínio Martins da Dardenne,Laurent Emmanuel Savino,Wilson Caffarena,Ernesto Raul |
author_role |
author |
author2 |
Dardenne,Laurent Emmanuel Savino,Wilson Caffarena,Ernesto Raul |
author2_role |
author author author |
dc.contributor.author.fl_str_mv |
Silva,João Hermínio Martins da Dardenne,Laurent Emmanuel Savino,Wilson Caffarena,Ernesto Raul |
dc.subject.por.fl_str_mv |
inflammation integrins VLA-4 docking molecular dynamics |
topic |
inflammation integrins VLA-4 docking molecular dynamics |
description |
The VLA-4 antigen (α4β1 integrin) is involved in the pathophysiology of a variety of diseases including asthma, multiple sclerosis, rheumatoid arthritis and diabetes. The ligand selectivity toward this integrin remains a difficult problem, mainly due to the fact that 3D structures of most integrins are still unknown. We initially built a 3D computational model of the α4β1 ligand binding site, taking the crystal structure of the integrin αVβ3 as template. Then, we performed a computational study on a set of seven α4β1 antagonists, evaluating the binding modes of 4-[N'-(2-methylphenyl)ureido]phenylacetyl and derivatives by molecular docking. Molecular dynamics simulations were used to improve the receptor-ligand energy landscape exploration by the docking algorithm. The compounds were systematically arranged in two main binding modes, and in all cases, pointed out that these antagonists preferably bind to the α4β1 integrin active site in an extended conformation that resembles the one in solution. LIE (linear interaction energy) calculations also confirmed this statement given that the most prevailing binding mode is also the energetically most favored one. This study benefits the comprehension of the mechanism of this family of antagonists and may provide useful information for rational drug design. |
publishDate |
2010 |
dc.date.none.fl_str_mv |
2010-01-01 |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532010000300022 |
url |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532010000300022 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
10.1590/S0103-50532010000300022 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
text/html |
dc.publisher.none.fl_str_mv |
Sociedade Brasileira de Química |
publisher.none.fl_str_mv |
Sociedade Brasileira de Química |
dc.source.none.fl_str_mv |
Journal of the Brazilian Chemical Society v.21 n.3 2010 reponame:Journal of the Brazilian Chemical Society (Online) instname:Sociedade Brasileira de Química (SBQ) instacron:SBQ |
instname_str |
Sociedade Brasileira de Química (SBQ) |
instacron_str |
SBQ |
institution |
SBQ |
reponame_str |
Journal of the Brazilian Chemical Society (Online) |
collection |
Journal of the Brazilian Chemical Society (Online) |
repository.name.fl_str_mv |
Journal of the Brazilian Chemical Society (Online) - Sociedade Brasileira de Química (SBQ) |
repository.mail.fl_str_mv |
||office@jbcs.sbq.org.br |
_version_ |
1750318170679279616 |