Molecular Modeling Suggests Cruzain Specificity for Peptide Primaquine Prodrugs

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dc.contributor.authorGoulart Trossini, Gustavo Henrique
dc.contributor.authorChin, Chung Man [UNESP]
dc.contributor.authorde Souza Menezes, Carla Maria
dc.contributor.authorFerreira, Elizabeth Igne [UNESP]
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.date.accessioned2014-05-20T13:24:56Z
dc.date.available2014-05-20T13:24:56Z
dc.date.issued2010-08-01
dc.description.abstractChagas' disease, infection caused by the protozoan Trypanosoma cruzi, is an important, social and medical ailment in the Latin America. This disease is endemic in 21 countries, mostly Latin America countries, with more than 300,000 new cases every year and about 16-18 million infected people. Current therapy is not effective in the chronic phase of the disease. Thus, new and better drugs are urgently needed. In this sense, the in vitro activity of primaquine (PQ) was reported. Based on this, peptide prodrugs of primaquine containing dipeptides - lysine-arginine (LysArg), phenylalanine-alanine (PheAla) and phenylalanine-arginine (PheArg) -- as carriers, were designed to be selectively cleaved by cruzain, a specific cysteine protease of T. cruzi. The prodrugs have shown to be active against tripomastigote forms according to this order: LysArg-PQ> PheAla-PQ> PheArg-PQ. The molecular mechanism of action considered a probable nucleophilic attack of the catalytic residue of cruzain (Cys25) on the respective prodrug amide carbonyl carbon, releasing PQ. In order to test this hypothesis, molecular modeling studies were performed, physicochemical parameters and stereoelectronic features calculated by using the AM1 semi-empirical method suggest that the amide carbonyl carbon is favorable for cleavage, where the LysArg showed the most electronic reactive and sterically disposable, leading to the prodrug release and action. In addition, the docking study indicates the occurrence of specific interactions between prodrugs and the pockets S1 and S2 of cruzain through the dipeptides carriers, being the distance between cruzain Cys25 and the amide carbonyl group related to the biological activity of the prodrugs.en
dc.description.affiliationUniv São Paulo, Fac Ciencias Farmaceut, Lapen Lab Planejamento & Sintese Quimioterap Pote, Dept Farm, BR-05389970 São Paulo, SP, Brazil
dc.description.affiliationUniv Estadual Paulista, Dept Farmacos & Medicamentos, Lapdesf Lab Desenvolvimento Farmacos, São Paulo, Brazil
dc.description.affiliationUnespUniv Estadual Paulista, Dept Farmacos & Medicamentos, Lapdesf Lab Desenvolvimento Farmacos, São Paulo, Brazil
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipIdFAPESP: 01/01192-3
dc.description.sponsorshipIdFAPESP: 08/58723-0
dc.description.sponsorshipIdCAPES: 00019 03-8
dc.format.extent528-533
dc.identifierhttp://dx.doi.org/10.2174/157018010791526287
dc.identifier.citationCartas In Drug Design & Discovery. Sharjah: Bentham Science Publ Ltd, v. 7, n. 7, p. 528-533, 2010.
dc.identifier.doi10.2174/157018010791526287
dc.identifier.issn1570-1808
dc.identifier.lattes9734333607975413
dc.identifier.orcid0000-0003-4141-0455
dc.identifier.scopus2-s2.0-77958495902
dc.identifier.urihttp://hdl.handle.net/11449/7868
dc.identifier.wosWOS:000280474100008
dc.language.isoeng
dc.publisherBentham Science Publ Ltd
dc.relation.ispartofCartas In Drug Design & Discovery
dc.relation.ispartofjcr0.924
dc.relation.ispartofsjr0,247
dc.rights.accessRightsAcesso restrito
dc.sourceWeb of Science
dc.subjectChagas' diseaseen
dc.subjectCruzainen
dc.subjectPeptide prodrugen
dc.subjectMolecular Modelingen
dc.subjectAM1 semi-empirical methoden
dc.subjectMolecular dockingen
dc.titleMolecular Modeling Suggests Cruzain Specificity for Peptide Primaquine Prodrugsen
dc.typeArtigo
dcterms.rightsHolderBentham Science Publ Ltd
unesp.author.lattes9734333607975413[2]
unesp.author.orcid0000-0003-4141-0455[2]
unesp.author.orcid0000-0003-3634-2531[1]
unesp.author.orcid0000-0003-2087-033X[4]
unesp.campusUniversidade Estadual Paulista (Unesp), Faculdade de Ciências Farmacêuticas, Araraquarapt

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