Combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.

Chagas' disease is caused by Trypanosoma cruzi, a protozoan transmitted to humans by blood-feeding insects, blood transfusion or congenitally. Previous research led us to discover a parasite proline racemase (TcPRAC) and to establish its validity as a target for the design of new chemotherapies...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Armand Berneman, Lory Montout, Sophie Goyard, Nathalie Chamond, Alain Cosson, Simon d'Archivio, Nicolas Gouault, Philippe Uriac, Arnaud Blondel, Paola Minoprio
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f1a53129aa5947b39770b326a747a493
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:f1a53129aa5947b39770b326a747a493
record_format	dspace
spelling	oai:doaj.org-article:f1a53129aa5947b39770b326a747a4932021-11-18T07:49:23ZCombined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.1932-620310.1371/journal.pone.0060955https://doaj.org/article/f1a53129aa5947b39770b326a747a4932013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23613764/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Chagas' disease is caused by Trypanosoma cruzi, a protozoan transmitted to humans by blood-feeding insects, blood transfusion or congenitally. Previous research led us to discover a parasite proline racemase (TcPRAC) and to establish its validity as a target for the design of new chemotherapies against the disease, including its chronic form. A known inhibitor of proline racemases, 2-pyrrolecarboxylic acid (PYC), is water-insoluble. We synthesized soluble pyrazole derivatives, but they proved weak or inactive TcPRAC inhibitors. TcPRAC catalytic site is too small and constrained when bound to PYC to allow efficient search for new inhibitors by virtual screening. Forty-nine intermediate conformations between the opened enzyme structure and the closed liganded one were built by calculating a transition path with a method we developed. A wider range of chemical compounds could dock in the partially opened intermediate active site models in silico. Four models were selected for known substrates and weak inhibitors could dock in them and were used to screen chemical libraries. Two identified soluble compounds, (E)-4-oxopent-2-enoic acid (OxoPA) and its derivative (E)-5-bromo-4-oxopent-2-enoic acid (Br-OxoPA), are irreversible competitive inhibitors that presented stronger activity than PYC on TcPRAC. We show here that increasing doses of OxoPA and Br-OxoPA hamper T. cruzi intracellular differentiation and fate in mammalian host cells. Our data confirm that through to their binding mode, these molecules are interesting and promising as lead compounds for the development of chemotherapies against diseases where active proline racemases play essential roles.Armand BernemanLory MontoutSophie GoyardNathalie ChamondAlain CossonSimon d'ArchivioNicolas GouaultPhilippe UriacArnaud BlondelPaola MinoprioPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e60955 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Armand Berneman Lory Montout Sophie Goyard Nathalie Chamond Alain Cosson Simon d'Archivio Nicolas Gouault Philippe Uriac Arnaud Blondel Paola Minoprio Combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.
description	Chagas' disease is caused by Trypanosoma cruzi, a protozoan transmitted to humans by blood-feeding insects, blood transfusion or congenitally. Previous research led us to discover a parasite proline racemase (TcPRAC) and to establish its validity as a target for the design of new chemotherapies against the disease, including its chronic form. A known inhibitor of proline racemases, 2-pyrrolecarboxylic acid (PYC), is water-insoluble. We synthesized soluble pyrazole derivatives, but they proved weak or inactive TcPRAC inhibitors. TcPRAC catalytic site is too small and constrained when bound to PYC to allow efficient search for new inhibitors by virtual screening. Forty-nine intermediate conformations between the opened enzyme structure and the closed liganded one were built by calculating a transition path with a method we developed. A wider range of chemical compounds could dock in the partially opened intermediate active site models in silico. Four models were selected for known substrates and weak inhibitors could dock in them and were used to screen chemical libraries. Two identified soluble compounds, (E)-4-oxopent-2-enoic acid (OxoPA) and its derivative (E)-5-bromo-4-oxopent-2-enoic acid (Br-OxoPA), are irreversible competitive inhibitors that presented stronger activity than PYC on TcPRAC. We show here that increasing doses of OxoPA and Br-OxoPA hamper T. cruzi intracellular differentiation and fate in mammalian host cells. Our data confirm that through to their binding mode, these molecules are interesting and promising as lead compounds for the development of chemotherapies against diseases where active proline racemases play essential roles.
format	article
author	Armand Berneman Lory Montout Sophie Goyard Nathalie Chamond Alain Cosson Simon d'Archivio Nicolas Gouault Philippe Uriac Arnaud Blondel Paola Minoprio
author_facet	Armand Berneman Lory Montout Sophie Goyard Nathalie Chamond Alain Cosson Simon d'Archivio Nicolas Gouault Philippe Uriac Arnaud Blondel Paola Minoprio
author_sort	Armand Berneman
title	Combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.
title_short	Combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.
title_full	Combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.
title_fullStr	Combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.
title_full_unstemmed	Combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.
title_sort	combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight chagas' disease.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/f1a53129aa5947b39770b326a747a493
work_keys_str_mv	AT armandberneman combinedapproachesfordrugdesignpointsthewaytonovelprolineracemaseinhibitorcandidatestofightchagasdisease AT lorymontout combinedapproachesfordrugdesignpointsthewaytonovelprolineracemaseinhibitorcandidatestofightchagasdisease AT sophiegoyard combinedapproachesfordrugdesignpointsthewaytonovelprolineracemaseinhibitorcandidatestofightchagasdisease AT nathaliechamond combinedapproachesfordrugdesignpointsthewaytonovelprolineracemaseinhibitorcandidatestofightchagasdisease AT alaincosson combinedapproachesfordrugdesignpointsthewaytonovelprolineracemaseinhibitorcandidatestofightchagasdisease AT simondarchivio combinedapproachesfordrugdesignpointsthewaytonovelprolineracemaseinhibitorcandidatestofightchagasdisease AT nicolasgouault combinedapproachesfordrugdesignpointsthewaytonovelprolineracemaseinhibitorcandidatestofightchagasdisease AT philippeuriac combinedapproachesfordrugdesignpointsthewaytonovelprolineracemaseinhibitorcandidatestofightchagasdisease AT arnaudblondel combinedapproachesfordrugdesignpointsthewaytonovelprolineracemaseinhibitorcandidatestofightchagasdisease AT paolaminoprio combinedapproachesfordrugdesignpointsthewaytonovelprolineracemaseinhibitorcandidatestofightchagasdisease
_version_	1718422947807363072

Combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.

Ejemplares similares