Doutorado em Medicina Tropical e Saúde Pública (IPTSP)
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Navegando Doutorado em Medicina Tropical e Saúde Pública (IPTSP) por Por Orientador "Andrade, Carolina Horta"
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Item Identificação de novos compostos bioativos contra tripanossomatídeos a partir de estratégias integradas em química medicinal(Universidade Federal de Goiás, 2018-04-02) Melo Filho, Cleber Camilo de; Braga, Rodolpho de Campos; http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4731114E4; Andrade, Carolina Horta; http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4745602P1; Andrade, Carolina Horta; Castro, Ana Maria de; Oliveira, Milton Adriano Pelli de; Lacerda, Elisângela de Paula Silveira; Scotti, Marcus TulliusTrypanosomatids are parasites that cause different diseases affecting mainly low-income populations from countries in development or underdeveloped countries. These diseases are classified as neglected tropical diseases (NTDs). The few drugs available for the treatment of these parasitic diseases present several problems regarding low efficacy, resistance, and toxicity, making the need of new therapeutic options an urgent task. In this sense, the aim of this work was the identification of novel drug candidates against trypanosomatids through the application of integrated strategies in Medicinal Chemistry. To achieve this goal, three studies were performed combining different computer assisted drug design (CADD) approaches and experimental validation. In the first study, 39 virtual hits were identified by quantitative structure activity relationships (QSAR)-based virtual screening (VS) and selected for experimental evaluation. Among them, 13 compounds were active and selective in vitro against intracellular T. cruzi. Additionally, an in silico multi-parameter analysis for evaluation and comparison of some pharmacokinetic (ADMET) and physicochemical properties, with potency and selectivity, allowed the prioritization of the most promising compounds for further in vivo assays. In the second study, VS was performed for identification of novel potential inhibitors of pyruvate kinase (PK) from Leishmania spp., allowing the discovery of 14 novel potential inhibitors of this enzyme. These compounds were submitted to experimental evaluation against L. infantum amastigotes. In the third study, a dual-target VS was performed, allowing the identification of 15 potential inhibitors of both PK and sterol 14 α-demethylase (CYP51) of Leishmania spp., also predicted as active compounds against L. infantum amastigotes by QSAR models. Therefore, this work has demonstrated the potential of the integration of computational and experimental methods for the identification of active compounds against trypanosomatids.Item Reposicionamento de fármacos e planejamento de novos compostos ativos contra Schistosoma mansoni(Universidade Federal de Goiás, 2016-11-01) Neves, Bruno Junior; Andrade, Carolina Horta; http://lattes.cnpq.br/2018317447324228; Andrade, Carolina Horta; Braga, Rodolpho de Campos; Bezerra, José Clecildo Barreto; Andricopulo, Adriano Defini; Silva Junior, Floriano PaesSchistosomiasis is a serious endemic disease caused by trematodes of the genus Schistosoma. Currently the control of this disease is based solely on the administration of praziquantel. However, its extensive use has raised concerns about the emergence of resistant worms and the need of discovering new anti-schistosomal drugs. Given the above, the main goal of this study was to design new S. mansoni thioredoxin glutathione reductase (SmTGR) inhibitors showing antischistosomal activity through cheminformatics tools and to repurpose new drugs for schistosomiasis employing bioinformatics tools. At the stage of drug design, binary QSAR models were constructed and validated to predict inhibitory activity of SmTGR, a validated target in schistosomes. From the individual models, consensus and consensus rigor models and were generated (CCRs = 0.87 and 0.91, respectively) and used for the virtual screening of 150,000 compounds. At the end of this process, 29 compounds were prioritized and purchased for biological evaluation. As a result, two new hits representing new molecular scaffolds showed EC 50 ≤ 3.5 µM to schistosomula and ≤ 6.0 µM for adult female worms, low cytotoxicity against WSS-1 mammalian cells (IC50 > 16 µM) and low reactivity with cysteine proteases (IC50 > 100 µM). In the second part of this work, that is drug repositioning, 2,114 proteins of S. mansoni were used in a search for orthologs in therapeutic drug target databases (DrugBank, TTD and STITCH). As a result, 215 drugs were predicted to interact with 49 schistosome proteins, of which 47 had already anti-schistosomal activity reported in the literature. Then, principal component analysis (PCA) and k-means showed that 115 drugs were in the chemical space of known anti-schistosomal agents, increasing the overall confidence of predictions. Among them, paroxetine (PAR), an antidepressant drug predicted to inhibit serotonin transporter proteins of S. mansoni (SmSERTs) presented antischistosomal activity against schistosomula (EC50 = 2.5 µM) and adult worms (EC50 = 5.1 µM and 9.9 µM for males and females respectively) of S. mansoni. Lastly, molecular docking studies with SmSERT-A and its ortholog in humans (hSERT) explored the molecular basis for antischistosomal activity of PAR and provided information for the design of more potent and selective analogs.Item Identificação de novos fármacos antimaláricos através de estratégia de quimiogenômica por reposicionamento e validação experimental(Universidade Federal de Goiás, 2018-03-05) Rodrigues, Juliana; Cravo, Pedro Vitor Lemos; http://lattes.cnpq.br/1059199347781390; Andrade, Carolina Horta; Andrade, Carolina Horta; Andrade, Éverton Kort Kamp; Castro, Ana Maria; Neves, Bruno Júnior; Costa, Fabio Trindade MaranhãoMalaria is an infectious disease of possible chronic evolution that affects billions of people in the tropics and subtropics. P. falciparum is the most lethal malaria parasite of humans, while P. vivax is the most widely distributed. The effectiveness of the antimalarial treatment is compromised by the ability of the parasite to evolve resistance to the compounds and by the lack of new effective antimalarials, underscoring the urgent need for the discovery of new drugs. One of the strategies that has been gradually explored in the search for new therapies is the so-called "drug repurposing" approach. In this context, the goal of the present study was to use a drug repurposing-chemogenomics strategy to identify effective drugs against malaria parasites. A comparative genomics tool available from the TDR Targets Database was used through to select targets expected to be present exclusively in P. falciparum and P. vivax parasites, but absent in humans. Each of the selected targets was then used as a query in the following databases: Drugbank, Therapeutic Target Database and STITCH. The P. falciparum and P. vivax targets were aligned with their predicted homologue targets, using pairwise BLAST, to compare functionally relevant regions. Only those where ≥ 80% overlap was observed between the two sequences for the corresponding drug target were considered for subsequent studies. Thereafter, the drugs identified were submitted to a bibliographic search to find drugs that were never evaluated against malaria parasites in the past. A prediction of active compounds was performed through binary QSAR models. The selected drugs were submitted to in vitro assays using asexual stages of P. falciparum (strains 3D7, chloroquine-sensitive, and W2, multidrug-resistant). Epirubicin displayed potent in vitro activity against the 3D7 strain (IC50 = 140 nM). In addition, the drug was shown to be about twice as active against the W2 resistant strain (IC50 = 69 nM), exhibiting even greater activity than chloroquine. At present, in vitro experiments in sexual stages (ookinete conversion) and in vivo assays with P. berghei and P. chabaudi are being carried out. In conclusion, epirubicin is a good antimalarial drug candidate, although future studies are required to investigate its mechanism of action, potential toxicity, and eventually, to advance in the drug development process.