Molecular dynamics of the interaction of Plasmodium falciparum and human serine hydroxymethyltransferase with 5-formyl-6-hydrofolic acid analogues: design of new potential antimalarials
Autor(a) principal: | |
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Data de Publicação: | 2006 |
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=S0103-50532006000700028 |
Resumo: | Plasmodium falciparum Serine Hydroxymethyltransferase has never been used as target for antimalarial chemotherapy, possibly because its great sequence similarity with the human enzyme. This similarity suggests implies that P. falciparum may not be able to mutate this enzyme to develop resistance for chemotherapy. In this work, we have used differences on the dynamic behavior of the active sites of the crystallographic structure of the human enzyme and a homology model of parasite's enzyme, both in complex with glycine, as N-glycine-[3-hydroxy-2-methyl-5-phosphonooxymethyl-pyridin-4-yl-methane] and 5-formyl-6-hydrofolic acid, to design prototypes for selective inhibitors of this enzyme as new potential antimalarials. Those potential inhibitors are 5-formyl-6-hydrofolic acid derivatives with different charges and tail lengths. Molecular dynamics simulations and interaction energy estimates of the compounds within the active sites of both enzymes showed that compounds with a negative net charge and either shorter tails or longer amphoteric tails, would be more selective towards pfSHMT. |
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Molecular dynamics of the interaction of Plasmodium falciparum and human serine hydroxymethyltransferase with 5-formyl-6-hydrofolic acid analogues: design of new potential antimalarialsantimalarial chemotherapydrug designmolecular dynamicsPlasmodium falciparum SHMTselective enzymatic inhibitionPlasmodium falciparum Serine Hydroxymethyltransferase has never been used as target for antimalarial chemotherapy, possibly because its great sequence similarity with the human enzyme. This similarity suggests implies that P. falciparum may not be able to mutate this enzyme to develop resistance for chemotherapy. In this work, we have used differences on the dynamic behavior of the active sites of the crystallographic structure of the human enzyme and a homology model of parasite's enzyme, both in complex with glycine, as N-glycine-[3-hydroxy-2-methyl-5-phosphonooxymethyl-pyridin-4-yl-methane] and 5-formyl-6-hydrofolic acid, to design prototypes for selective inhibitors of this enzyme as new potential antimalarials. Those potential inhibitors are 5-formyl-6-hydrofolic acid derivatives with different charges and tail lengths. Molecular dynamics simulations and interaction energy estimates of the compounds within the active sites of both enzymes showed that compounds with a negative net charge and either shorter tails or longer amphoteric tails, would be more selective towards pfSHMT.Sociedade Brasileira de Química2006-12-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersiontext/htmlhttp://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532006000700028Journal of the Brazilian Chemical Society v.17 n.7 2006reponame:Journal of the Brazilian Chemical Society (Online)instname:Sociedade Brasileira de Química (SBQ)instacron:SBQ10.1590/S0103-50532006000700028info:eu-repo/semantics/openAccessFrança,Tanos C. C.Wilter,AlanRamalho,Teodorico C.Pascutti,Pedro G.Figueroa-Villar,José D.eng2007-01-29T00:00:00Zoai:scielo:S0103-50532006000700028Revistahttp://jbcs.sbq.org.brONGhttps://old.scielo.br/oai/scielo-oai.php||office@jbcs.sbq.org.br1678-47900103-5053opendoar:2007-01-29T00:00Journal of the Brazilian Chemical Society (Online) - Sociedade Brasileira de Química (SBQ)false |
dc.title.none.fl_str_mv |
Molecular dynamics of the interaction of Plasmodium falciparum and human serine hydroxymethyltransferase with 5-formyl-6-hydrofolic acid analogues: design of new potential antimalarials |
title |
Molecular dynamics of the interaction of Plasmodium falciparum and human serine hydroxymethyltransferase with 5-formyl-6-hydrofolic acid analogues: design of new potential antimalarials |
spellingShingle |
Molecular dynamics of the interaction of Plasmodium falciparum and human serine hydroxymethyltransferase with 5-formyl-6-hydrofolic acid analogues: design of new potential antimalarials França,Tanos C. C. antimalarial chemotherapy drug design molecular dynamics Plasmodium falciparum SHMT selective enzymatic inhibition |
title_short |
Molecular dynamics of the interaction of Plasmodium falciparum and human serine hydroxymethyltransferase with 5-formyl-6-hydrofolic acid analogues: design of new potential antimalarials |
title_full |
Molecular dynamics of the interaction of Plasmodium falciparum and human serine hydroxymethyltransferase with 5-formyl-6-hydrofolic acid analogues: design of new potential antimalarials |
title_fullStr |
Molecular dynamics of the interaction of Plasmodium falciparum and human serine hydroxymethyltransferase with 5-formyl-6-hydrofolic acid analogues: design of new potential antimalarials |
title_full_unstemmed |
Molecular dynamics of the interaction of Plasmodium falciparum and human serine hydroxymethyltransferase with 5-formyl-6-hydrofolic acid analogues: design of new potential antimalarials |
title_sort |
Molecular dynamics of the interaction of Plasmodium falciparum and human serine hydroxymethyltransferase with 5-formyl-6-hydrofolic acid analogues: design of new potential antimalarials |
author |
França,Tanos C. C. |
author_facet |
França,Tanos C. C. Wilter,Alan Ramalho,Teodorico C. Pascutti,Pedro G. Figueroa-Villar,José D. |
author_role |
author |
author2 |
Wilter,Alan Ramalho,Teodorico C. Pascutti,Pedro G. Figueroa-Villar,José D. |
author2_role |
author author author author |
dc.contributor.author.fl_str_mv |
França,Tanos C. C. Wilter,Alan Ramalho,Teodorico C. Pascutti,Pedro G. Figueroa-Villar,José D. |
dc.subject.por.fl_str_mv |
antimalarial chemotherapy drug design molecular dynamics Plasmodium falciparum SHMT selective enzymatic inhibition |
topic |
antimalarial chemotherapy drug design molecular dynamics Plasmodium falciparum SHMT selective enzymatic inhibition |
description |
Plasmodium falciparum Serine Hydroxymethyltransferase has never been used as target for antimalarial chemotherapy, possibly because its great sequence similarity with the human enzyme. This similarity suggests implies that P. falciparum may not be able to mutate this enzyme to develop resistance for chemotherapy. In this work, we have used differences on the dynamic behavior of the active sites of the crystallographic structure of the human enzyme and a homology model of parasite's enzyme, both in complex with glycine, as N-glycine-[3-hydroxy-2-methyl-5-phosphonooxymethyl-pyridin-4-yl-methane] and 5-formyl-6-hydrofolic acid, to design prototypes for selective inhibitors of this enzyme as new potential antimalarials. Those potential inhibitors are 5-formyl-6-hydrofolic acid derivatives with different charges and tail lengths. Molecular dynamics simulations and interaction energy estimates of the compounds within the active sites of both enzymes showed that compounds with a negative net charge and either shorter tails or longer amphoteric tails, would be more selective towards pfSHMT. |
publishDate |
2006 |
dc.date.none.fl_str_mv |
2006-12-01 |
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=S0103-50532006000700028 |
url |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532006000700028 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
10.1590/S0103-50532006000700028 |
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.17 n.7 2006 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 |
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1750318167433936896 |