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Adriano de Paula Sabinohttp://lattes.cnpq.br/2875593207169323Vinícius Gonçalves MaltarolloMichell de Oliveira AlmeidaAdolfo Henrique de Moraes Silvahttp://lattes.cnpq.br/5491097022431830Alessandra Loures Rocha2022-07-04T19:01:53Z2022-07-04T19:01:53Z2020-11-30http://hdl.handle.net/1843/42887As leucemias são neoplasias malignas caracterizadas pela proliferação de células imaturas do sistema hematopoiético. A Leucemia Mieloide Aguda (LMA) é uma neoplasia maligna caracterizada pelo acúmulo de mieloblastos na medula óssea e sangue periférico, sendo uma das leucemias mais prevalentes no adulto. A heterogeneidade genômica da doença dificulta o estabelecimento de protocolos de tratamento. Já a Leucemia Mieloide Crônica (LMC) é uma doença mieloproliferativa rara caracterizada pelo acúmulo de células mieloides e presença do cromossomo Philadelfia (Ph). Os inibidores de tirosina quinase são os principais agentes quimioterápicos disponíveis, porém existem pacientes que não respondem adequadamente ao tratamento. Portanto, a busca por novos compostos com atividade antitumoral é justificada. Neste trabalho foi realizado estudo in silico para a busca dos alvos proteicos de nove compostos com atividade antitumoral conhecida frente às linhagens THP-1 e K562. Três desses compostos são triterpenos (1 ao 3) e seis são análogos alcaloides de 3-alquilpiridina (4, 5, 6, 7, 8 e 9). Foi utilizada a metodologia de target fishing para a busca dos alvos, baseado no princípio da similaridade em que moléculas semelhantes podem se ligar aos mesmos alvos. O banco de dados ChEMBL foi utilizado na busca de moléculas com atividade citotóxica frente às linhagens THP-1 e K562, para em seguida serem comparadas aos compostos de interesse por meio do cálculo do coeficiente de Tanimoto (Tc), que avalia a similaridade entre moléculas. O Tc foi calculado usando os fingerprints MACCS e PubChem. Os compostos com valores de Tc maiores ou igual a 0,75 foram considerados para a pesquisa bibliográfica de alvos já descritos na literatura. Outra estratégia foi o uso de servidores para a predição de alvo molecular. As proteínas 6-fosfofruto-2-quinase/frutose-2,6-bifosfatase 3 (PFKFB3) e nicotinamida fosforibosiltransferase (NAMT) foram indicadas como possíveis alvos para o composto 7 e a fosfatase 2 indutora da fase M (CDC25B) para os compostos 1 e 3. As estruturas cristalográficas desses potenciais alvos foram obtidas por meio do Protein Data Bank (PDB). Os compostos 7, 1 e 3 foram submetidos a simulações de acoplamento molecular com o programa GOLD. O estudo in silico foi bem-sucedido na busca de alvos moleculares para o composto 7, visto que interações importantes descritas na literatura com o sítio de ligação das proteínas PFKFB3 e NAMPT foram observadas. Por outro lado, os compostos 1 e 3 não se ligaram no sítio de ligação da proteína CDC25B de forma favorável.Leukemias are malignant neoplasms characterized by the proliferation of immature cells of the hematopoietic system. Acute Myeloid Leukemia (AML) is a malignant neoplasm characterized by the accumulation of myeloblasts in the bone marrow and peripheral blood, being one of the most prevalent leukemias in adults. The genomic heterogeneity of the disease makes it difficult to establish treatment protocols. On the other hand, Chronic Myeloid Leukemia (CML) is a rare myeloproliferative disease characterized by the accumulation of myeloid cells and the presence of the Philadelfia (Ph) chromosome. Tyrosine kinase inhibitors are the main chemotherapeutic agents available, but there are patients who do not respond adequately to treatment. Therefore, the search for new compounds with antitumor activity is justified. In this work, an in silico study was carried out to search for protein targets for nine compounds with known antitumor activity against the THP-1 and K562 strains. Three compounds are triterpenes (1 to 3) and six are alkaloid analogs of 3-alkylpyridine (4, 5, 6, 7, 8 and 9). The target fishing methodology was used to search for targets, based on the principle of similarity in which similar molecules can bind to the same targets. The ChEMBL database was used to search for molecules with cytotoxic activity against the THP-1 and K562 strains, to then be compared to the compounds of interest by calculating the Tanimoto coefficient (Tc), which assesses the similarity between molecules. The Tc was calculated using the MACCS and PubChem fingerprints. Compounds with Tc values greater than or equal to 0.75 were considered for the bibliographic search of targets already described in the literature. Another strategy was the use of servers for the prediction of molecular targets. The proteins 6- phosphofruct-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and nicotinamide phosphoribosyltransferase (NAMPT) were indicated as possible targets for compound 7 and phase M inducing phosphatase 2 (CDC25B) for the compounds 1 and 3. The crystallographic structures of these potential targets were obtained using the Protein Data Bank (PDB). Compounds 7, 1 and 3 were submitted to docking simulations with the GOLD program. The in silico study was successful in the search for molecular targets for compound 7, since important interactions described in the literature with the binding site of the PFKFB3 and NAMPT proteins were observed. On the other hand, compounds 1 and 3 did not bind at the CDC25B protein binding site favorably.porUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em Análises Clínicas e ToxicológicasUFMGBrasilFARMACIA - FACULDADE DE FARMACIAhttp://creativecommons.org/licenses/by-nc-nd/3.0/pt/info:eu-repo/semantics/openAccessLeucemiaTriterpenosAnálogos alcaloides de 3-alquilpiridinaAlvo molecularTarget fishingAcoplamento molecularEstudo in silico de potenciais alvos proteicos para moléculas citotóxicas em linhagens de células leucêmicas humanas.info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALDissertação Alessandra final 03-11-2022-Completa.pdfDissertação Alessandra final 03-11-2022-Completa.pdfapplication/pdf2131532https://repositorio.ufmg.br/bitstream/1843/42887/4/Disserta%c3%a7%c3%a3o%20Alessandra%20final%2003-11-2022-Completa.pdf436d6e82cd428150d361cd5eaa1d399dMD54CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8811https://repositorio.ufmg.br/bitstream/1843/42887/2/license_rdfcfd6801dba008cb6adbd9838b81582abMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82119https://repositorio.ufmg.br/bitstream/1843/42887/3/license.txt34badce4be7e31e3adb4575ae96af679MD531843/428872022-11-04 06:58:54.626oai:repositorio.ufmg.br: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Repositório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2022-11-04T09:58:54Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
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