Reposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimental
Autor(a) principal: | |
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Data de Publicação: | 2015 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFG |
Texto Completo: | http://repositorio.bc.ufg.br/tede/handle/tede/11605 |
Resumo: | Leishmaniases are diseases caused by more than 20 protozoan parasites belonging to the genus Leishmania, and transmitted through the bite of infected female Phlebotomine and Lutzomya. An estimated 20,000 to 30,000 deaths and 1.3 million new cases occur annually. Currently available drugs have serious limitations regarding their efficacy and especially their toxicity, side effects and costs. Thus, there is a pressing need for new therapies that are safer and more effective. Due to the high costs of traditional process of drug discovery and development, alternative strategies have been developed to speed up this process, and reducing its costs. Among them, is drug repositioning, which is the discovery of new therapeutic applications for drugs already on the market. The aim of this work was to search and identify approved and clinically available drugs with potential antileishmanial activity, using bio- and cheminformatics approaches, and experimental validation of these drugs using in vitro assays. Initially, we generated a dataset of Leishmania genes with orthologs in four species (L. major, L. braziliensis, L. infantum e L. mexicana), specific to the genus Leishmania, trying to explore potential molecular targets that could be effective against all species and essential to the process of development and differentiation of the parasite. This dataset was used to interrogate three databases of approved drugs (DrugBank and TTD) aiming to identify homologues of validated targets for other diseases. Furthermore, binary QSAR models were generated from phenotypic assay data, using different descriptors, and two machine learning methods, and then consensus models were built. Homology search allowed the identification of 36 new potential molecular targets that need to be validated experimentally, and 122 drugs. Of these 122 compounds, 28 were previously reported on the literature as actives. Five drugs not yet tested were selected for biological screening in vitro against promastigotes (lansoprazole, ibuprofen, sertaconzole, nilutamide and clomifen). Three of them showed activity at 100 μM and we determined their IC50. Ibuprofen showed an IC50 of 55.08 μM, sertaconazole IC50 < 15 μM and clomifen (IC50 5,75 μM, more potent than the standard drug (pentamidine IC50 = 7,24), suggesting a potential activity. Besides that, the QSAR models generated had adequate statistical parameters, especially for consensus models. One of the models generated by consensus was employed to predict the activity of the drugs identified by the bioinformatics approach. The best models can be used as filters in a virtual screening process. In vitro assays in the promastigote form of L. amazonensis were standardized, and used to successfully identify new potential candidates for drug repositioning. |
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Andrade, Carolina Hortahttp://lattes.cnpq.br/2018317447324228Andrade, Carolina HortaCravo, Pedro Vitor LemosSilva Junior, Floriano Paeshttp://lattes.cnpq.br/3135658719787376Silva, Diego Cabral2021-08-30T12:09:12Z2021-08-30T12:09:12Z2015-08-04SILVA, D. C. Reposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimental. 2015. 112 f. Dissertação (Mestrado em Medicina Tropical e Saúde Publica) - Universidade Federal de Goiás, Goiânia, 2015.http://repositorio.bc.ufg.br/tede/handle/tede/11605ark:/38995/001300000d7z4Leishmaniases are diseases caused by more than 20 protozoan parasites belonging to the genus Leishmania, and transmitted through the bite of infected female Phlebotomine and Lutzomya. An estimated 20,000 to 30,000 deaths and 1.3 million new cases occur annually. Currently available drugs have serious limitations regarding their efficacy and especially their toxicity, side effects and costs. Thus, there is a pressing need for new therapies that are safer and more effective. Due to the high costs of traditional process of drug discovery and development, alternative strategies have been developed to speed up this process, and reducing its costs. Among them, is drug repositioning, which is the discovery of new therapeutic applications for drugs already on the market. The aim of this work was to search and identify approved and clinically available drugs with potential antileishmanial activity, using bio- and cheminformatics approaches, and experimental validation of these drugs using in vitro assays. Initially, we generated a dataset of Leishmania genes with orthologs in four species (L. major, L. braziliensis, L. infantum e L. mexicana), specific to the genus Leishmania, trying to explore potential molecular targets that could be effective against all species and essential to the process of development and differentiation of the parasite. This dataset was used to interrogate three databases of approved drugs (DrugBank and TTD) aiming to identify homologues of validated targets for other diseases. Furthermore, binary QSAR models were generated from phenotypic assay data, using different descriptors, and two machine learning methods, and then consensus models were built. Homology search allowed the identification of 36 new potential molecular targets that need to be validated experimentally, and 122 drugs. Of these 122 compounds, 28 were previously reported on the literature as actives. Five drugs not yet tested were selected for biological screening in vitro against promastigotes (lansoprazole, ibuprofen, sertaconzole, nilutamide and clomifen). Three of them showed activity at 100 μM and we determined their IC50. Ibuprofen showed an IC50 of 55.08 μM, sertaconazole IC50 < 15 μM and clomifen (IC50 5,75 μM, more potent than the standard drug (pentamidine IC50 = 7,24), suggesting a potential activity. Besides that, the QSAR models generated had adequate statistical parameters, especially for consensus models. One of the models generated by consensus was employed to predict the activity of the drugs identified by the bioinformatics approach. The best models can be used as filters in a virtual screening process. In vitro assays in the promastigote form of L. amazonensis were standardized, and used to successfully identify new potential candidates for drug repositioning.As leishmanioses são doenças causadas por protozoários do gênero Leishmania, sendo transmitidas pela picada de insetos vetores pertencentes aos gêneros Phlebotomus e Lutzomya. São estimadas 30.000 mortes e 1,3 milhões de novos casos por ano. Atualmente, a farmacoterapia disponível apresenta grandes limitações no que concerne à eficácia e, principalmente, à elevada toxicidade, efeitos adversos e alto custo de algumas terapias. Por estas razões, é premente a necessidade de novas alternativas terapêuticas que sejam mais eficazes. Devido ao alto custo do processo tradicional de descoberta e desenvolvimento de novos fármacos, estratégias alternativas vêm sendo desenvolvidas para acelerar e economizar esse processo. Dentre elas, destaca-se o reposicionamento de fármacos, que consiste em buscar novas aplicações terapêuticas para fármacos disponíveis no mercado. O objetivo do presente trabalho foi a busca e identificação de fármacos aprovados e disponíveis no mercado com potencial atividade leishmanicida, utilizando técnicas de bio- e quimioinformática, e, posteriormente, a avaliação experimental desses fármacos em ensaios in vitro contra formas amastigotas e promastigotas de Leishmania. Inicialmente, construiu-se um banco de dados de genes de Leishmania com ortólogos em quatro espécies (L. major, L. braziliensis, L. infantum e L.mexicana), e específicos do gênero Leishmania, tentando explorar potenciais alvos moleculares efetivos contra todas as espécies e essenciais ao processo de diferencição e desenvolvimento do parasito. Esse banco de dados foi utilizado para interrogar 2 bases de dados de fármacos aprovados (DrugBank, TTD), na tentativa de identificar alvos homólogos validados para outras doenças. Além disso, foram gerados modelos de relação quantitativa entre estrutura e atividade (QSAR) binários, a partir de dados de ensaios fenotípicos disponíveis na literatura, utilizando diferentes descritores e 2 métodos de aprendizado de máquina; posteriormente foram construídos modelos por consenso, combinando os modelos individuais. A estratégia de busca por homologia permitiu a identificação de 36 novos possíveis alvos moleculares, que precisam ser validados experimentalmente, e 122 fármacos. Desses 122 compostos, 28 tem atividade leishmanicida reportada na literatura, demonstrando a alta capacidade dessa estratégia em identificar essas moléculas. Cinco dos fármacos selecionados por essa metodologia foram avaliados in vitro contra formas promastigota do parasito (lansoprazol, ibuprofeno, sertaconzol, nilutamida e clomifeno) e três apresentaram atividade (mais de 50% de morte dos parasitos) na triagem biológica com 100 μM. Esses fármacos (ibuprofeno, sertaconzol, e clomifeno) foram encaminhados para determinação da concentração efetiva em 50%. Ibuprofeno apresentou CE50 de 55,08 μM, e Sertaconazol CE50 < 15 μM. A CE50 do clomifeno 5,75 μM ficou abaixo da CE50 da pentamidina (7,24), fármaco padrão, sugerindo um potencial de atividade interessante. Além disso, os modelos de QSAR gerados apresentaram parâmetros estatísticos adequados, especialmente os modelos por consenso. Um dos modelos por consenso foi utilizado para predizer a atividade dos fármacos identificados pela estratégia de bioinformática. Além disso, eles podem ser utilizados como filtros em processo de triagem virtual, ajudando na seleção de mais compostos potencialmente ativos. O presente trabalho foi efetivo na identificação de fármacos com potencial para serem reposicionados para leishmanioseSubmitted by Luciana Ferreira (lucgeral@gmail.com) on 2021-08-27T11:39:32Z No. of bitstreams: 2 Dissertação - Diego Cabral Silva - 2015.pdf: 3581780 bytes, checksum: 32d1a19cfe27676e6c6f126d5499e72d (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5)Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2021-08-30T12:09:12Z (GMT) No. of bitstreams: 2 Dissertação - Diego Cabral Silva - 2015.pdf: 3581780 bytes, checksum: 32d1a19cfe27676e6c6f126d5499e72d (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5)Made available in DSpace on 2021-08-30T12:09:12Z (GMT). No. of bitstreams: 2 Dissertação - Diego Cabral Silva - 2015.pdf: 3581780 bytes, checksum: 32d1a19cfe27676e6c6f126d5499e72d (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5) Previous issue date: 2015-08-04Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqporUniversidade Federal de GoiásPrograma de Pós-graduação em Medicina Tropical e Saúde Publica (IPTSP)UFGBrasilInstituto de Patologia Tropical e Saúde Pública - IPTSP (RG)Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessLeishmanioseReposicionamento de fármacosBioinformáticaQSARTriagem virtualEnsaios in vitroLeishmaniasisDrug repositioningBioinformaticsQSARVirtual screeningIn vitro assaysCIENCIAS BIOLOGICAS::PARASITOLOGIA::PROTOZOOLOGIA DE PARASITOSReposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimentalDrug repositioning for Leishmania spp: in silico strategies and experimental evaluationinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesis72500500500500289590reponame:Repositório Institucional da UFGinstname:Universidade Federal de Goiás (UFG)instacron:UFGLICENSElicense.txtlicense.txttext/plain; charset=utf-81748http://repositorio.bc.ufg.br/tede/bitstreams/55cebaac-1356-480a-b002-473ec35b5f78/download8a4605be74aa9ea9d79846c1fba20a33MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8805http://repositorio.bc.ufg.br/tede/bitstreams/62b16f7a-260b-4f8c-98c2-904e19b4c449/download4460e5956bc1d1639be9ae6146a50347MD52ORIGINALDissertação - Diego Cabral Silva - 2015.pdfDissertação - Diego Cabral Silva - 2015.pdfapplication/pdf3581780http://repositorio.bc.ufg.br/tede/bitstreams/9a5be888-51cc-44dd-a30f-b77242dcbce2/download32d1a19cfe27676e6c6f126d5499e72dMD53tede/116052021-08-30 09:09:13.53http://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 Internationalopen.accessoai:repositorio.bc.ufg.br:tede/11605http://repositorio.bc.ufg.br/tedeRepositório InstitucionalPUBhttp://repositorio.bc.ufg.br/oai/requesttasesdissertacoes.bc@ufg.bropendoar:2021-08-30T12:09:13Repositório Institucional da UFG - Universidade Federal de Goiás (UFG)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 |
dc.title.pt_BR.fl_str_mv |
Reposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimental |
dc.title.alternative.eng.fl_str_mv |
Drug repositioning for Leishmania spp: in silico strategies and experimental evaluation |
title |
Reposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimental |
spellingShingle |
Reposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimental Silva, Diego Cabral Leishmaniose Reposicionamento de fármacos Bioinformática QSAR Triagem virtual Ensaios in vitro Leishmaniasis Drug repositioning Bioinformatics QSAR Virtual screening In vitro assays CIENCIAS BIOLOGICAS::PARASITOLOGIA::PROTOZOOLOGIA DE PARASITOS |
title_short |
Reposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimental |
title_full |
Reposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimental |
title_fullStr |
Reposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimental |
title_full_unstemmed |
Reposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimental |
title_sort |
Reposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimental |
author |
Silva, Diego Cabral |
author_facet |
Silva, Diego Cabral |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Andrade, Carolina Horta |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/2018317447324228 |
dc.contributor.referee1.fl_str_mv |
Andrade, Carolina Horta |
dc.contributor.referee2.fl_str_mv |
Cravo, Pedro Vitor Lemos |
dc.contributor.referee4.fl_str_mv |
Silva Junior, Floriano Paes |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/3135658719787376 |
dc.contributor.author.fl_str_mv |
Silva, Diego Cabral |
contributor_str_mv |
Andrade, Carolina Horta Andrade, Carolina Horta Cravo, Pedro Vitor Lemos Silva Junior, Floriano Paes |
dc.subject.por.fl_str_mv |
Leishmaniose Reposicionamento de fármacos Bioinformática QSAR Triagem virtual Ensaios in vitro |
topic |
Leishmaniose Reposicionamento de fármacos Bioinformática QSAR Triagem virtual Ensaios in vitro Leishmaniasis Drug repositioning Bioinformatics QSAR Virtual screening In vitro assays CIENCIAS BIOLOGICAS::PARASITOLOGIA::PROTOZOOLOGIA DE PARASITOS |
dc.subject.eng.fl_str_mv |
Leishmaniasis Drug repositioning Bioinformatics QSAR Virtual screening In vitro assays |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS::PARASITOLOGIA::PROTOZOOLOGIA DE PARASITOS |
description |
Leishmaniases are diseases caused by more than 20 protozoan parasites belonging to the genus Leishmania, and transmitted through the bite of infected female Phlebotomine and Lutzomya. An estimated 20,000 to 30,000 deaths and 1.3 million new cases occur annually. Currently available drugs have serious limitations regarding their efficacy and especially their toxicity, side effects and costs. Thus, there is a pressing need for new therapies that are safer and more effective. Due to the high costs of traditional process of drug discovery and development, alternative strategies have been developed to speed up this process, and reducing its costs. Among them, is drug repositioning, which is the discovery of new therapeutic applications for drugs already on the market. The aim of this work was to search and identify approved and clinically available drugs with potential antileishmanial activity, using bio- and cheminformatics approaches, and experimental validation of these drugs using in vitro assays. Initially, we generated a dataset of Leishmania genes with orthologs in four species (L. major, L. braziliensis, L. infantum e L. mexicana), specific to the genus Leishmania, trying to explore potential molecular targets that could be effective against all species and essential to the process of development and differentiation of the parasite. This dataset was used to interrogate three databases of approved drugs (DrugBank and TTD) aiming to identify homologues of validated targets for other diseases. Furthermore, binary QSAR models were generated from phenotypic assay data, using different descriptors, and two machine learning methods, and then consensus models were built. Homology search allowed the identification of 36 new potential molecular targets that need to be validated experimentally, and 122 drugs. Of these 122 compounds, 28 were previously reported on the literature as actives. Five drugs not yet tested were selected for biological screening in vitro against promastigotes (lansoprazole, ibuprofen, sertaconzole, nilutamide and clomifen). Three of them showed activity at 100 μM and we determined their IC50. Ibuprofen showed an IC50 of 55.08 μM, sertaconazole IC50 < 15 μM and clomifen (IC50 5,75 μM, more potent than the standard drug (pentamidine IC50 = 7,24), suggesting a potential activity. Besides that, the QSAR models generated had adequate statistical parameters, especially for consensus models. One of the models generated by consensus was employed to predict the activity of the drugs identified by the bioinformatics approach. The best models can be used as filters in a virtual screening process. In vitro assays in the promastigote form of L. amazonensis were standardized, and used to successfully identify new potential candidates for drug repositioning. |
publishDate |
2015 |
dc.date.issued.fl_str_mv |
2015-08-04 |
dc.date.accessioned.fl_str_mv |
2021-08-30T12:09:12Z |
dc.date.available.fl_str_mv |
2021-08-30T12:09:12Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
SILVA, D. C. Reposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimental. 2015. 112 f. Dissertação (Mestrado em Medicina Tropical e Saúde Publica) - Universidade Federal de Goiás, Goiânia, 2015. |
dc.identifier.uri.fl_str_mv |
http://repositorio.bc.ufg.br/tede/handle/tede/11605 |
dc.identifier.dark.fl_str_mv |
ark:/38995/001300000d7z4 |
identifier_str_mv |
SILVA, D. C. Reposicionamento de fármacos para Leishmania spp: estratégias “in silico” e avaliação experimental. 2015. 112 f. Dissertação (Mestrado em Medicina Tropical e Saúde Publica) - Universidade Federal de Goiás, Goiânia, 2015. ark:/38995/001300000d7z4 |
url |
http://repositorio.bc.ufg.br/tede/handle/tede/11605 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.program.fl_str_mv |
72 |
dc.relation.confidence.fl_str_mv |
500 500 500 500 |
dc.relation.department.fl_str_mv |
28 |
dc.relation.cnpq.fl_str_mv |
959 |
dc.relation.sponsorship.fl_str_mv |
0 |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Goiás |
dc.publisher.program.fl_str_mv |
Programa de Pós-graduação em Medicina Tropical e Saúde Publica (IPTSP) |
dc.publisher.initials.fl_str_mv |
UFG |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Instituto de Patologia Tropical e Saúde Pública - IPTSP (RG) |
publisher.none.fl_str_mv |
Universidade Federal de Goiás |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFG instname:Universidade Federal de Goiás (UFG) instacron:UFG |
instname_str |
Universidade Federal de Goiás (UFG) |
instacron_str |
UFG |
institution |
UFG |
reponame_str |
Repositório Institucional da UFG |
collection |
Repositório Institucional da UFG |
bitstream.url.fl_str_mv |
http://repositorio.bc.ufg.br/tede/bitstreams/55cebaac-1356-480a-b002-473ec35b5f78/download http://repositorio.bc.ufg.br/tede/bitstreams/62b16f7a-260b-4f8c-98c2-904e19b4c449/download http://repositorio.bc.ufg.br/tede/bitstreams/9a5be888-51cc-44dd-a30f-b77242dcbce2/download |
bitstream.checksum.fl_str_mv |
8a4605be74aa9ea9d79846c1fba20a33 4460e5956bc1d1639be9ae6146a50347 32d1a19cfe27676e6c6f126d5499e72d |
bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 |
repository.name.fl_str_mv |
Repositório Institucional da UFG - Universidade Federal de Goiás (UFG) |
repository.mail.fl_str_mv |
tasesdissertacoes.bc@ufg.br |
_version_ |
1811721516882067456 |