Planejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania major
Autor(a) principal: | |
---|---|
Data de Publicação: | 2015 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UEFS |
Texto Completo: | http://localhost:8080/tede/handle/tede/279 |
Resumo: | According to WHO, Leishmaniasis is the second most important disease caused by protozoans. However, the available therapeutic arsenal for its treatment is limited and has low efficacy and safety profile. Once Leishmania ssp. are pteridine auxotrophs key enzymes of the folate metabolism have been targeted to circumvent this dilemma. However, Dihydrofolate Reductase-Thymidylate Synthase (DHFR-TS) inhibitors are ineffective against Leishmania major due to an alternative folate pathway regulated by Pteridine Reductase 1 (PTR1). Thus, identifying molecules that act on both enzymes is crucial to develop new leishmanicidal drugs. For that reason, the main goal of this study is to identify, through in silico approaches, (pharmacophore models), putative PTR1 inhibitors that also show structural requirements for L. major DHFR-TS inhibition. The pharmacophore models 10 and 20, PTR1 (2 H-bond donors, 4 H-bond acceptors and 3 hydrophobic centers) and DHFR-TS inhibitors (2 H-bond acceptors and 2 hydrophobic centers) respectively, show high performance to differentiate true-binders from decoys (AUCPTR1=0.90; AUCDHFR-TS=0.86) and to explain the structure-activity relationships for the inhibitors under study. Thus, these models were employed sequentially to select 10 molecules whose effect over the thermal stability of LmPTR1 was investigated by ThermoFluor?. According to this assay, two molecules stabilize LmPTR1: Z80393 (?Tm = 1.02?C) and Z33165 (?Tm = 0.9?C). Binding displacement assays with biopterin or NADPH showed that Z80393 binds within the substrate binding site, whereas Z33165 binds in the cofactor binding site. Z80303 effect over the catalytic activity of PTR1 was investigated by fluorimetry. This approach allowed us to determine the inhibitor?s potency (IC50=32.31 ? 1.18 ?M). Finally, Z80303 putative binding profile was generated by molecular docking and analyzed by Molecular Dynamics (productive phase= 15 ns). The results show that during 70% of the simulation, Z80393 H-bonds to Ser-111 and Arg-17 residues. Therefore, this study not only led to identification of a new class of LmPTR1 inhibitors, but also allowed us to determine its potency, mode of inhibition and binding profile towards its therapeutic target. |
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Castilho, Marcelo Santos01231045566http://lattes.cnpq.br/6921231386745339Leite, Franco Henrique Andrade2016-01-13T23:50:52Z2015-11-06LEITE, Franco Henrique Andrade. Planejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania major. 2015. 156 f. Tese (Doutorado Acad?mico em Biotecnologia)- Universidade Estadual de Feira de Santana, Feira de Santana, 2015.http://localhost:8080/tede/handle/tede/279According to WHO, Leishmaniasis is the second most important disease caused by protozoans. However, the available therapeutic arsenal for its treatment is limited and has low efficacy and safety profile. Once Leishmania ssp. are pteridine auxotrophs key enzymes of the folate metabolism have been targeted to circumvent this dilemma. However, Dihydrofolate Reductase-Thymidylate Synthase (DHFR-TS) inhibitors are ineffective against Leishmania major due to an alternative folate pathway regulated by Pteridine Reductase 1 (PTR1). Thus, identifying molecules that act on both enzymes is crucial to develop new leishmanicidal drugs. For that reason, the main goal of this study is to identify, through in silico approaches, (pharmacophore models), putative PTR1 inhibitors that also show structural requirements for L. major DHFR-TS inhibition. The pharmacophore models 10 and 20, PTR1 (2 H-bond donors, 4 H-bond acceptors and 3 hydrophobic centers) and DHFR-TS inhibitors (2 H-bond acceptors and 2 hydrophobic centers) respectively, show high performance to differentiate true-binders from decoys (AUCPTR1=0.90; AUCDHFR-TS=0.86) and to explain the structure-activity relationships for the inhibitors under study. Thus, these models were employed sequentially to select 10 molecules whose effect over the thermal stability of LmPTR1 was investigated by ThermoFluor?. According to this assay, two molecules stabilize LmPTR1: Z80393 (?Tm = 1.02?C) and Z33165 (?Tm = 0.9?C). Binding displacement assays with biopterin or NADPH showed that Z80393 binds within the substrate binding site, whereas Z33165 binds in the cofactor binding site. Z80303 effect over the catalytic activity of PTR1 was investigated by fluorimetry. This approach allowed us to determine the inhibitor?s potency (IC50=32.31 ? 1.18 ?M). Finally, Z80303 putative binding profile was generated by molecular docking and analyzed by Molecular Dynamics (productive phase= 15 ns). The results show that during 70% of the simulation, Z80393 H-bonds to Ser-111 and Arg-17 residues. Therefore, this study not only led to identification of a new class of LmPTR1 inhibitors, but also allowed us to determine its potency, mode of inhibition and binding profile towards its therapeutic target.A leishmaniose tem sido indicada pela OMS como a segunda protozoose mais importante em termos de mortalidade e preval?ncia. Entretanto, o repert?rio de f?rmacos dispon?veis ? limitado e apresenta, na maioria dos casos, baixos ?ndices de efic?cia e seguran?a. Embora os protozo?rios do g?nero Leishmania sejam auxotr?ficos para folatos, inibidores da Diidrofolato Redutase-Timidilato Sintase (DHFR-TS) s?o pouco eficazes contra esse parasito. A baixa suscetibilidade se explica pela presen?a da Pteridina Redutase 1 (PTR1) que atua como via alternativa para a redu??o de ?cido f?lico ou de pteridinas n?o conjugadas, quando DHFR-TS est? inibida. Diante desse cen?rio, mol?culas que atuam sobre PTR1 e DHFR-TS de Leishmania ssp. parecem ser promissoras para o desenvolvimento de f?rmacos contra a leishmaniose. Por essa raz?o, o objetivo desse trabalho foi identificar, por triagem in silico (modelo farmacof?rico), potenciais inibidores de PTR1 que apresentem os requisitos estruturais m?nimos para inibir tamb?m DHFR de L. major. Os modelos farmacof?ricos 10 e 20, baseados em inibidores de PTR1 (2 doadores de lig. H, 4 aceitadores de lig. H e 3 centros hidrof?bicos) e DHFR-TS (2 aceitadores de lig. H e 2 centros hidrof?bicos) respectivamente, mostraram desempenho satisfat?rio em discriminar inibidores verdadeiros de falsos positivos (AUCPTR1=0,90; AUCDHFR-TS=0,86), al?m de explicarem a rela??o entre a estrutura qu?mica e a atividade biol?gica. Esses modelos foram usados sequencialmente para selecionar 10 mol?culas que tiveram seu efeito sobre a estabilidade t?rmica de LmPTR1 investigado por ThermoFluor?. Nesse ensaio foram identificadas duas mol?culas que estabilizaram LmPTR1: Z80393 (?Tm = 1,02?C) e Z33165 (?Tm = 0,9?C). Ensaios de deslocamento com biopterina ou NADPH mostraram que Z80393 compete com o substrato, enquanto Z33165 interage no s?tio do cofator. O efeito de Z80393 sobre a atividade catal?tica de LmPTR1 foi investigado por fluorimetria, permitindo determinar a pot?ncia desse inibidor (IC50=32,31 ? 1,18 ?M). Por fim, um modelo de intera??o para esse inibidor foi gerado por acoplamento molecular e a pose obtida foi analisada atrav?s de uma Din?mica Molecular com fase produtiva de 15 ns. Os resultados obtidos mostram que durante 70% da simula??o, Z80393 faz liga??es de H com os res?duos Ser-111 e Arg-17. Portanto, o presente trabalho n?o s? levou a identifica??o de uma nova classe de inibidores de LmPTR1, mas tamb?m permitiu caracterizar sua pot?ncia, modalidade de inibi??o e perfil de intera??o com seu alvo terap?utico.Submitted by Ricardo Cedraz Duque Moliterno (ricardo.moliterno@uefs.br) on 2016-01-13T23:50:52Z No. of bitstreams: 1 TESE-FINAL-FRANCO-HENRIQUE-CORRIGIDO-V4.pdf: 27152448 bytes, checksum: 7d448c937bb21040514eedeaa37f689f (MD5)Made available in DSpace on 2016-01-13T23:50:52Z (GMT). No. of bitstreams: 1 TESE-FINAL-FRANCO-HENRIQUE-CORRIGIDO-V4.pdf: 27152448 bytes, checksum: 7d448c937bb21040514eedeaa37f689f (MD5) Previous issue date: 2015-11-06Conselho Nacional de Pesquisa e Desenvolvimento Cient?fico e Tecnol?gico - CNPqapplication/pdfporUniversidade Estadual de Feira de SantanaDoutorado Acad?mico em BiotecnologiaUEFSBrasilDEPARTAMENTO DE CI?NCIAS BIOL?GICASDin?mica molecularDHFR-TSFluorimetriaModelos farmacof?ricosPTR1ThermoFluor?Molecular dynamicsFluorometryPharmacophore modelsCIENCIAS DA SAUDE::FARMACIAPlanejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania majorinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis-6815269229789791543600600600600502612338345058928269976364134497549961802873727776104890info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UEFSinstname:Universidade Estadual de Feira de Santana (UEFS)instacron:UEFSORIGINALTESE-FINAL-FRANCO-HENRIQUE-CORRIGIDO-V4.pdfTESE-FINAL-FRANCO-HENRIQUE-CORRIGIDO-V4.pdfapplication/pdf27152448http://tede2.uefs.br:8080/bitstream/tede/279/2/TESE-FINAL-FRANCO-HENRIQUE-CORRIGIDO-V4.pdf7d448c937bb21040514eedeaa37f689fMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82089http://tede2.uefs.br:8080/bitstream/tede/279/1/license.txt7b5ba3d2445355f386edab96125d42b7MD51tede/2792016-01-13 21:33:05.597oai:tede2.uefs.br:8080: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Biblioteca Digital de Teses e Dissertaçõeshttp://tede2.uefs.br:8080/PUBhttp://tede2.uefs.br:8080/oai/requestbcuefs@uefs.br|| bcref@uefs.br||bcuefs@uefs.bropendoar:2016-01-14T00:33:05Biblioteca Digital de Teses e Dissertações da UEFS - Universidade Estadual de Feira de Santana (UEFS)false |
dc.title.por.fl_str_mv |
Planejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania major |
title |
Planejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania major |
spellingShingle |
Planejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania major Leite, Franco Henrique Andrade Din?mica molecular DHFR-TS Fluorimetria Modelos farmacof?ricos PTR1 ThermoFluor? Molecular dynamics Fluorometry Pharmacophore models CIENCIAS DA SAUDE::FARMACIA |
title_short |
Planejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania major |
title_full |
Planejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania major |
title_fullStr |
Planejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania major |
title_full_unstemmed |
Planejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania major |
title_sort |
Planejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania major |
author |
Leite, Franco Henrique Andrade |
author_facet |
Leite, Franco Henrique Andrade |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Castilho, Marcelo Santos |
dc.contributor.authorID.fl_str_mv |
01231045566 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/6921231386745339 |
dc.contributor.author.fl_str_mv |
Leite, Franco Henrique Andrade |
contributor_str_mv |
Castilho, Marcelo Santos |
dc.subject.por.fl_str_mv |
Din?mica molecular DHFR-TS Fluorimetria Modelos farmacof?ricos PTR1 ThermoFluor? |
topic |
Din?mica molecular DHFR-TS Fluorimetria Modelos farmacof?ricos PTR1 ThermoFluor? Molecular dynamics Fluorometry Pharmacophore models CIENCIAS DA SAUDE::FARMACIA |
dc.subject.eng.fl_str_mv |
Molecular dynamics Fluorometry Pharmacophore models |
dc.subject.cnpq.fl_str_mv |
CIENCIAS DA SAUDE::FARMACIA |
description |
According to WHO, Leishmaniasis is the second most important disease caused by protozoans. However, the available therapeutic arsenal for its treatment is limited and has low efficacy and safety profile. Once Leishmania ssp. are pteridine auxotrophs key enzymes of the folate metabolism have been targeted to circumvent this dilemma. However, Dihydrofolate Reductase-Thymidylate Synthase (DHFR-TS) inhibitors are ineffective against Leishmania major due to an alternative folate pathway regulated by Pteridine Reductase 1 (PTR1). Thus, identifying molecules that act on both enzymes is crucial to develop new leishmanicidal drugs. For that reason, the main goal of this study is to identify, through in silico approaches, (pharmacophore models), putative PTR1 inhibitors that also show structural requirements for L. major DHFR-TS inhibition. The pharmacophore models 10 and 20, PTR1 (2 H-bond donors, 4 H-bond acceptors and 3 hydrophobic centers) and DHFR-TS inhibitors (2 H-bond acceptors and 2 hydrophobic centers) respectively, show high performance to differentiate true-binders from decoys (AUCPTR1=0.90; AUCDHFR-TS=0.86) and to explain the structure-activity relationships for the inhibitors under study. Thus, these models were employed sequentially to select 10 molecules whose effect over the thermal stability of LmPTR1 was investigated by ThermoFluor?. According to this assay, two molecules stabilize LmPTR1: Z80393 (?Tm = 1.02?C) and Z33165 (?Tm = 0.9?C). Binding displacement assays with biopterin or NADPH showed that Z80393 binds within the substrate binding site, whereas Z33165 binds in the cofactor binding site. Z80303 effect over the catalytic activity of PTR1 was investigated by fluorimetry. This approach allowed us to determine the inhibitor?s potency (IC50=32.31 ? 1.18 ?M). Finally, Z80303 putative binding profile was generated by molecular docking and analyzed by Molecular Dynamics (productive phase= 15 ns). The results show that during 70% of the simulation, Z80393 H-bonds to Ser-111 and Arg-17 residues. Therefore, this study not only led to identification of a new class of LmPTR1 inhibitors, but also allowed us to determine its potency, mode of inhibition and binding profile towards its therapeutic target. |
publishDate |
2015 |
dc.date.issued.fl_str_mv |
2015-11-06 |
dc.date.accessioned.fl_str_mv |
2016-01-13T23:50:52Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
LEITE, Franco Henrique Andrade. Planejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania major. 2015. 156 f. Tese (Doutorado Acad?mico em Biotecnologia)- Universidade Estadual de Feira de Santana, Feira de Santana, 2015. |
dc.identifier.uri.fl_str_mv |
http://localhost:8080/tede/handle/tede/279 |
identifier_str_mv |
LEITE, Franco Henrique Andrade. Planejamento e avalia??o de novos inibidores de Pteridina Redutase 1 (PTR1) de Leishmania major. 2015. 156 f. Tese (Doutorado Acad?mico em Biotecnologia)- Universidade Estadual de Feira de Santana, Feira de Santana, 2015. |
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por |
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por |
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UEFS |
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DEPARTAMENTO DE CI?NCIAS BIOL?GICAS |
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