Desenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitro

Detalhes bibliográficos
Autor(a) principal: Castro, Larissa Henriques Evangelista
Data de Publicação: 2021
Tipo de documento: Tese
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da UFRRJ
Texto Completo: https://tede.ufrrj.br/jspui/handle/jspui/6553
Resumo: Chagas disease (CD) is a neglected tropical disease caused by the parasite Trypanosoma cruzi and presents millions of cases in several countries. Currently there are no vaccines for CD prevention and there are only two drugs for its treatment, but in Brazil, only benzonidazole is used and is ineffective on disease?s chronic phase. Thus, research for new drugs becomes essential. The enzyme sterol 14?-desmethylase (CYP51) belongs to the ergosterol biosynthesis pathway, which are fundamental for the integrity of the T. cruzi?s cell membrane. Its inhibition causes the parasite?s death and it can be promoted by the coordination of heterocyclic compounds with the iron atom of the enzyme?s heme group. On a previous work, a theoretical model of activity prediction for new inhibitors of CYP51 (T. cruzi), based on experimental and theoretical parameters calculated by molecular modeling, which was used for design new triazole piperine derivatives. On this current work, the original theoretical model was optimized using the semi-empirical PM7 method instead of PM6 and a selectivity study was done by molecular docking of heterocyclic compounds in T. cruzi?s CYP51 and H. sapiens?s CYP51. The most promising compounds, planned by the original model, were synthesized, evaluated in vitro against T. cruzi and they were tested for CYP51 inhibition. The new model presented a multiple correlation coefficient slightly higher than the original. The docking study indicates a likely selectivity of the compounds for the parasite?s enzyme. The compounds showed activities against trypomastigote forms, in agreement with the general predictions made by the model, and low cytotoxicity in primate cells. Preliminary enzyme inhibition assays indicated that the compounds designed with the model are in fact capable of inhibiting the parasite's CYP51.
id UFRRJ-1_4fb3523bd132f60cbde312f1b41d748e
oai_identifier_str oai:localhost:jspui/6553
network_acronym_str UFRRJ-1
network_name_str Biblioteca Digital de Teses e Dissertações da UFRRJ
repository_id_str
spelling Sant?Anna, Carlos Mauricio Rabello de827.232.227-72Lima, Marco Edilson Freire deIfa, Demian RochaSant' Anna, Carlos Maur?cio Rabello deLima, Aurea Echevarria Aznar NevesGraebin, Cedric StephanTrossini, Gustavo Henrique GoulartRodrigues, Daniel Alencar142.560.187-19http://lattes.cnpq.br/2174763588443208Castro, Larissa Henriques Evangelista2023-05-02T21:27:15Z2021-12-16CASTRO, Larissa Henriques Evangelista. Desenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitro. 2021. 175 p. Tese (Doutorado em Qu?mica, Qu?mica Org?nica) - Instituto de Qu?mica, Universidade Federal Rural do Rio de Janeiro. Serop?dica, RJ, 2021.https://tede.ufrrj.br/jspui/handle/jspui/6553Chagas disease (CD) is a neglected tropical disease caused by the parasite Trypanosoma cruzi and presents millions of cases in several countries. Currently there are no vaccines for CD prevention and there are only two drugs for its treatment, but in Brazil, only benzonidazole is used and is ineffective on disease?s chronic phase. Thus, research for new drugs becomes essential. The enzyme sterol 14?-desmethylase (CYP51) belongs to the ergosterol biosynthesis pathway, which are fundamental for the integrity of the T. cruzi?s cell membrane. Its inhibition causes the parasite?s death and it can be promoted by the coordination of heterocyclic compounds with the iron atom of the enzyme?s heme group. On a previous work, a theoretical model of activity prediction for new inhibitors of CYP51 (T. cruzi), based on experimental and theoretical parameters calculated by molecular modeling, which was used for design new triazole piperine derivatives. On this current work, the original theoretical model was optimized using the semi-empirical PM7 method instead of PM6 and a selectivity study was done by molecular docking of heterocyclic compounds in T. cruzi?s CYP51 and H. sapiens?s CYP51. The most promising compounds, planned by the original model, were synthesized, evaluated in vitro against T. cruzi and they were tested for CYP51 inhibition. The new model presented a multiple correlation coefficient slightly higher than the original. The docking study indicates a likely selectivity of the compounds for the parasite?s enzyme. The compounds showed activities against trypomastigote forms, in agreement with the general predictions made by the model, and low cytotoxicity in primate cells. Preliminary enzyme inhibition assays indicated that the compounds designed with the model are in fact capable of inhibiting the parasite's CYP51.A doen?a de Chagas (DC) ? uma doen?a tropical negligenciada causada pelo parasito Trypanosoma cruzi e apresenta milh?es de casos em v?rios pa?ses. Atualmente, n?o existem vacinas que previnam a DC e s? dois f?rmacos s?o usados para o tratamento. No Brasil, apenas o benzonidazol ? usado e ? pouco eficaz na fase cr?nica da doen?a. Dessa forma, pesquisas por novos f?rmacos tornam-se fundamentais. A enzima esterol 14?-desmetilase (CYP51) faz parte da via de bioss?ntese de ergoster?is, que s?o fundamentais para a integridade da membrana celular do T. cruzi. A sua inibi??o causa a morte do parasito e pode ser promovida pela coordena??o de compostos heteroc?clicos com o ?tomo de ferro do grupo heme da enzima. Em trabalho anterior, foi constru?do um modelo de previs?o de atividade te?rica de compostos na CYP51 (T. cruzi), baseado em par?metros experimentais e te?ricos calculados por modelagem molecular, que foi usado no planejamento de compostos triaz?licos derivados da piperina. No presente trabalho, o modelo te?rico original foi otimizado usando o m?todo semi-emp?rico PM7 no lugar do PM6 e um estudo de uma poss?vel seletividade foi feito pela docagem dos compostos heteroc?clicos na CYP51 de T. cruzi e de H. sapiens. Dos compostos planejados com o modelo original, os mais promissores foram sintetizados, tiveram suas atividades determinadas in vitro contra o T. cruzi e foram testados para a inibi??o da CYP51. O novo modelo apresentou um coeficiente de correla??o m?ltipla levemente superior ao do original. O estudo de docagem indica uma prov?vel seletividade dos compostos para a enzima do parasito. Os derivados apresentaram atividades contra as formas tripomastigotas, em acordo com as previs?es feitas pelo modelo e baixa citotoxicidade em c?lulas de primatas. Ensaios preliminares de inibi??o enzim?tica indicaram que os compostos planejados pelo modelo s?o capazes de inibir, de fato, a CYP51 do parasito.Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2023-05-02T21:27:15Z No. of bitstreams: 1 2021 - Larissa Henriques Evangelista Castro.pdf: 7382938 bytes, checksum: 0f6d9dd3eab2a65b6e1d58680ba9fbba (MD5)Made available in DSpace on 2023-05-02T21:27:15Z (GMT). No. of bitstreams: 1 2021 - Larissa Henriques Evangelista Castro.pdf: 7382938 bytes, checksum: 0f6d9dd3eab2a65b6e1d58680ba9fbba (MD5) Previous issue date: 2021-12-16CAPES - Coordena??o de Aperfei?oamento de Pessoal de N?vel SuperiorCNPq - Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gicoFAPERJ - Funda??o Carlos Chagas Filho de Amparo ? Pesquisa do Estado do Rio de Janeiroapplication/pdfhttps://tede.ufrrj.br/retrieve/73068/2021%20-%20Larissa%20Henriques%20Evangelista%20Castro.pdf.jpgporUniversidade Federal Rural do Rio de JaneiroPrograma de P?s-Gradua??o em Qu?micaUFRRJBrasilInstituto de Qu?micaALARC?N DE NOYA, B. et al. Large Urban Outbreak of Orally Acquired Acute Chagas Disease at a School in Caracas, Venezuela. The Journal of Infectious Diseases, v. 201, n. 9, p. 1308?1315, maio 2010. ALC?CER, L. Introdu??o ? qu?mica qu?ntica computacional. Rio de Janeiro: IST Press, Lisboa, 2007. AMINPOUR, M.; MONTEMAGNO, C.; TUSZYNSKI, J. A. An Overview of Molecular Modeling for Drug Discovery with Specific Illustrative Examples of Applications. Molecules, v. 24, n. 9, 2019. ANDRIANI, G. et al. Antitrypanosomal lead discovery: Identification of a ligandefficient inhibitor of Trypanosoma cruzi CYP51 and parasite growth. Journal of Medicinal Chemistry, v. 56, n. 6, p. 2556?2567, 2013. BARRY, M. A. et al. A therapeutic nanoparticle vaccine against Trypanosoma cruzi in a BALB/c mouse model of Chagas disease. Human vaccines & immunotherapeutics, v. 12, n. 4, p. 976?987, 2 abr. 2016. BASTOS, C. J. C. et al. Clinical outcomes of thirteen patients with acute chagas disease acquired through oral transmission from two urban outbreaks in Northeastern Brazil. PLoS Neglected Tropical Diseases, v. 4, n. 6, jun. 2010. BELL, L. et al. Evaluation of fluorescence- and mass spectrometry-based CYP inhibition assays for use in drug discovery. Journal of Biomolecular Screening, v. 13, n. 5, p. 343?353, 2008. BEN?TEZ, D. et al. Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids. PLoS Neglected Tropical Diseases, v. 10, n. 4, 12 abr. 2016. BERN, C. et al. Evaluation and treatment of chagas disease in the United States: A systematic reviewJournal of the American Medical AssociationJAMA, , 14 nov. 2007. Dispon?vel em: <https://pubmed.ncbi.nlm.nih.gov/18000201/>. Acesso em: 1 set. 2020 BOIANI, M. et al. Mode of action of Nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi: Is oxidative stress involved? Biochemical Pharmacology, v. 79, n. 12, p. 1736?1745, 15 jun. 2010. BRONOWSKA, A. K. Thermodynamics of Ligand-Protein Interactions: Implications for Molecular Design. Thermodynamics - Interaction Studies - Solids, Liquids and Gases, 2 nov. 2011. BROOIJMANS, N.; KUNTZ, I. D. Molecular Recognition and Docking Algorithms. Annual Review of Biophysics and Biomolecular Structure, v. 32, n. 1, p. 335?373, 28 jun. 2003. Bruker, APEX2 and SAINT Programs for Data Reduction, APEX2, SAINT and SADABS. (2013) Bruker AXS Inc., Madison, Wisconsin, USA. , 2013. Bruker, APEX2, SAINT and SADABS, APEX II. (2009) Bruker AXS Inc., Madison, Wisconsin, USA. , 2009. CALDAS, I. S.; SANTOS, E. G.; NOVAES, R. D. An evaluation of benznidazole as a Chagas disease therapeutic. https://doi.org/10.1080/14656566.2019.1650915, v. 20, n. 15, p. 1797?1807, 13 out. 2019. CANSIZ, A. et al. 4-Allyl-5-pyridin-4-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione: Synthesis, experimental and theoretical characterization. Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, v. 91, p. 136?145, jun. 2012. CASBARRA, L.; PROCACCI, P. Binding free energy predictions in host-guest systems using Autodock4. A retrospective analysis on SAMPL6, SAMPL7 and SAMPL8 challenges. Journal of Computer-Aided Molecular Design, v. 35, n. 6, p. 721?729, 1 jun. 2021. CASTRO, L. H. E. Constru??o de um Modelo de Previs?o de Atividade para o Planejamento e S?ntese de Triaz?is Promissores para Inibi??o da CYP51 de Trypanosoma cruzi.Disserta??o (Mestrado em Qu?mica) Serop?dica, 2016. CERECETTO, H.; GONZ?LEZ, M. Antiparasitic prodrug nifurtimox: revisiting its activation mechanism. Future microbiology, v. 6, n. 8, p. 847?850, 23 ago. 2011. CHAGAS, C. J. R. Nova entidade m?rbida do homem. Resumo geral de estudos etiol?jicos e cl?nicos. Mem?rias do Instituto Oswaldo, p. 219?275, 1909. CHAMBERS, C. C. et al. Model for aqueous solvation based on class IV atomic charges and first solvation shell effects. Journal of Physical Chemistry, v. 100, n. 40, p. 16385?16398, 3 out. 1996. CHATELAIN, E. Chagas disease drug discovery: Toward a new eraJournal of Biomolecular ScreeningSAGE Publications Inc., , 30 jan. 2015. Dispon?vel em: <https://pubmed.ncbi.nlm.nih.gov/25245987/>. Acesso em: 1 set. 2020 CHEN, C.-K. et al. Structural Characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei Bound to the Antifungal Drugs Posaconazole and Fluconazole. PLoS Neglected Tropical Diseases, v. 4, n. 4, p. e651, 6 abr. 2010. CHEN, H.-S.; MENG, H.-H.; CHENG, K.-C. A survey of methods used for the identification and characterization of inks. Forensic Science Journal, v. 1, n. 1, p. 1?14, 2002. CHRISTENSEN, A. S. et al. Semiempirical Quantum Mechanical Methods for Noncovalent Interactions for Chemical and Biochemical Applications. Chemical Reviews, v. 116, n. 9, p. 5301?5337, 11 maio 2016. CLAYDEN, J.; GREEVES, N.; WARREN, S. Organic Chemistry. 2nd. ed. [s.l.] Oxford University Press (OUP), 2012. COLODETTE, N. M. et al. Novel phosphatidylinositol 4-kinases III beta (PI4KIII?) inhibitors discovered by virtual screening using free energy models. Journal of Computer- Aided Molecular Design, v. 34, n. 10, p. 1091?1103, 1 out. 2020. CONTEH, L.; ENGELS, T.; MOLYNEUX, D. H. Socioeconomic aspects of neglected tropical diseases. Lancet (London, England), v. 375, n. 9710, p. 239?247, 2010. CORT?S-RUIZ, E. M. et al. Computational Methods to Discover Compounds for the Treatment of Chagas Disease. In: Advances in Protein Chemistry and Structural Biology. [s.l.] Academic Press Inc., 2018. v. 113p. 119?142. COURA, J. R. Transmission of chagasic infection by oral route in the natural history of Chagas disease. Rev Soc Bras Med Trop, v. 39 (Supl., p. 113?117, 2006. COURA, J. R. Chagas disease: What is known and what is needed - A background article. Memorias do Instituto Oswaldo Cruz. Anais...Fundacao Oswaldo Cruz, 2007. . Acesso em: 5 maio. 2020 COURA, J. R. The main sceneries of chagas disease transmission. The vectors, blood and oral transmissions - A comprehensive review. Memorias do Instituto Oswaldo Cruz, v. 110, n. 3, p. 277?282, 2015. COURA, J. R.; BORGES-PEREIRA, J. Chronic phase of Chagas disease: Why should it be treated? A comprehensive reviewMemorias do Instituto Oswaldo CruzFundacao Oswaldo Cruz, , 2011. Dispon?vel em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074- 02762011000600001&lng=en&nrm=iso&tlng=en>. Acesso em: 1 set. 2020 COURA, J. R.; CASTRO, S. L. DE. A Critical Review on Chagas Disease Chemotherapy. Mem?rias do Instituto Oswaldo Cruz, v. 97, n. 1, p. 3?24, jan. 2002. COURA, J. R.; DIAS, J. C. P. Epidemiology, control and surveillance of Chagas disease - 100 years after its discovery. Memorias do Instituto Oswaldo Cruz, v. 104, n. SUPPL. 1, p. 31?40, 2009. COURA, J. R.; V?AS, P. A. Chagas disease: A new worldwide challengeNature, 24 jun. 2010. Dispon?vel em: <http://www.nature.com/articles/nature09221>. Acesso em: 5 maio. 2020 CRAMER, C. J.; TRUHLAR, D. G. PM3-SM3: A general parameterization for including aqueous solvation effects in the PM3 molecular orbital model. Journal of Computational Chemistry, v. 13, n. 9, p. 1089?1097, 1 nov. 1992. DA COSTA FILHO, P. A.; POPPI, R. J. Algoritmo gen?tico em qu?mica. Qu?mica Nova, v. 22, n. 3, p. 405?411, 1999. DAUCHY, F.-A. et al. Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model. PLOS Neglected Tropical Diseases, v. 10, n. 11, p. e0005125, 17 nov. 2016. DE NOYA, B. A. et al. Update on oral chagas disease outbreaks in Venezuela: Epidemiological, clinical and diagnostic approaches. Memorias do Instituto Oswaldo Cruz, v. 110, n. 3, p. 377?386, 2015. DE OLIVEIRA, C. S. et al. Synthetic Approaches and Pharmacological Activity of 1,3,4-Oxadiazoles: A Review of the Literature from 2000?2012. Molecules 2012, Vol. 17, Pages 10192-10231, v. 17, n. 9, p. 10192?10231, 27 ago. 2012. DE PAULA, V. F. et al. Synthesis and insecticidal activity of new amide derivatives of piperine. Pest Manag Sci, v. 56, p. 168?174, 2000. DE RYCKER, M. et al. Challenges and recent progress in drug discovery for tropical diseasesNatureNature Publishing Group, , 26 jul. 2018. Dispon?vel em: <https://pubmed.ncbi.nlm.nih.gov/30046073/>. Acesso em: 1 set. 2020 DE SOUZA, W.; RODRIGUES, J. C. F. Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs. Interdisciplinary Perspectives on Infectious Diseases, v. 2009, p. 1?19, 2009. DEWAR, M. J. S. et al. AM1: A New General Purpose Quantum Mechanical Molecular Model1. Journal of the American Chemical Society, v. 107, n. 13, p. 3902? 3909, 1985. DEWAR, M. J. S.; THIEL, W. Ground states of molecules. 38. The MNDO method. Approximations and parameters. J. Am. Chem. Soc., v. 99, p. 4899?4907, 1977. DIAS, J. P. et al. Acute Chagas disease outbreak associated with oral transmission. Revista da Sociedade Brasileira de Medicina Tropical, v. 41, n. 3, p. 296?300, 2008. DIMASI, J. A.; GRABOWSKI, H. G.; HANSEN, R. W. Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics, v. 47, p. 20?33, 1 maio 2016. DNDi | Symptoms, transmission, and current treatments for Chagas disease. Dispon?vel em: <https://dndi.org/diseases/chagas/facts/>. Acesso em: 5 dez. 2021. Doen?a de Chagas ? Portugu?s (Brasil). Dispon?vel em: <https://www.gov.br/saude/pt-br/assuntos/saude-de-a-a-z/d/doenca-de-chagas>. Acesso em: 5 dez. 2021. ELDRIDGE, M. D. et al. Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. Journal of Computer-Aided Molecular Design, v. 11, n. 5, p. 425?445, 1997. FAUNDEZ, M. et al. Buthionine sulfoximine increases the toxicity of nifurtimox and benznidazole to Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy, v. 49, n. 1, p. 126?130, jan. 2005. FEASEY, N. et al. Neglected tropical diseases. British medical bulletin, v. 93, n. 1, p. 179?200, mar. 2010. FERREIRA, W. S. Utiliza??o da piperina como prot?tipo na s?ntese de novos antichag?sicos da classe das 1,3,4- tiadiaz?lio-2- fenilaminidasSerop?dica, Rio de Janeiro, 2006. FERREIRA, W. S. et al. Piperine, its Analogues and Derivatives: Potencial as Antiparasitic Drugs. Revista Virtual de Qu?mica, v. 4, n. 3, p. 208?224, 2012. FRADERA, X.; BABAOGLU, K. Overview of Methods and Strategies for Conducting Virtual Small Molecule ScreeningCurrent protocols in chemical biologyCurr Protoc Chem Biol, , 14 set. 2017. Dispon?vel em: <https://pubmed.ncbi.nlm.nih.gov/28910858/>. Acesso em: 28 jun. 2021 FRAN?A, R. R. F. et al. Inibidores potentes da enzima esterol 14?-desmetilase contra Trypanosoma cruzi. Revista Virtual de Quimica, v. 6, n. 5, p. 1483?1516, 2014. FRANKLIM, T. N. et al. Design, synthesis and trypanocidal evaluation of novel 1,2,4-triazoles-3- thiones derived from natural piperine. Molecules, v. 18, n. 6, p. 6366? 6382, 2013. FRANKLIM, T. N. et al. Design, Synthesis, Trypanocidal Activity, and Studies on Human Albumin Interaction of Novel S-Alkyl-1,2,4-triazoles. Article J. Braz. Chem. Soc, v. 30, n. 7, p. 1378?1394, 2019. FRAUCHES-SANTOS, C. S?NTESE E AVALIA??O DA ATIVIDADE ANTICORROSIVA DE CLORETOS DE 1, 3, 4-TIADIAZ?LIO-2-FENILAMINAS E 1, 3, 4- TRIAZ?LIO-2-TIOLATOS EM MEIO ?CIDOSerop?dica, Rio de Janeiro, 2017. FREIRE-DE-LIMA, L. et al. The toxic effects of piperine against Trypanosoma cruzi: ultrastructural alterations and reversible blockage of cytokinesis in epimastigote forms. Parasitology Research, v. 102 (5), 2008. FRIGGERI, L. et al. Validation of Human Sterol 14?-Demethylase (CYP51) Druggability: Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors. Journal of Medicinal Chemistry, v. 62, n. 22, p. 10391?10401, 27 nov. 2019. GASCON, J.; BERN, C.; PINAZO, M.-J. Chagas disease in Spain, the United States and other non-endemic countries. Acta Tropica, v. 115, n. 1?2, p. 22?27, jul. 2010. GIULIVI, C.; TURRENS, J. F.; BOVERIS, A. Chemiluminescence enhancement by trypanocidal drugs and by inhibitors of antioxidant enzymes in Trypanosoma cruzi. Molecular and Biochemical Parasitology, v. 30, n. 3, p. 243?251, 1 set. 1988. GONZ?LEZ-MEDINA, M. et al. Open chemoinformatic resources to explore the structure, properties and chemical space of moleculesRSC AdvancesRoyal Society of Chemistry, , 21 nov. 2017. Dispon?vel em: <https://pubs.rsc.org/en/content/articlehtml/2017/ra/c7ra11831g>. Acesso em: 11 out. 2020 GROS, L. et al. New azasterols against Trypanosoma brucei: Role of 24-sterol methyltransferase in inhibitor action. Antimicrobial Agents and Chemotherapy, v. 50, n. 8, p. 2595?2601, ago. 2006. GUEDES-DA-SILVA, F. H. et al. Antitrypanosomal activity of sterol 14?- demethylase (CYP51) inhibitors VNI and VFV in the swiss mouse models of chagas disease induced by the Trypanosoma cruzi Y strain. Antimicrobial Agents and Chemotherapy, v. 61, n. 4, 1 abr. 2017. HARGROVE, T. Y. et al. A requirement for an active proton delivery network supports a compound I-mediated C???C bond cleavage in CYP51 catalysis. 2020a. HARGROVE, T. Y. et al. A requirement for an active proton delivery network supports a compound I-mediated C?C bond cleavage in CYP51 catalysis. Journal of Biological Chemistry, v. 295, n. 29, p. 9998?10007, 17 jul. 2020b. HAUBRICH, B. A. et al. Discovery of an ergosterol-signaling factor that regulates trypanosoma brucei growth. Journal of Lipid Research, v. 56, n. 2, p. 331?341, 1 fev. 2015. HERNANDEZ, L. M. et al. Brote de Chagas agudo en Lebrija, Santander 2008Revista Del Observatorio de Salud P?blica de SantanderRevista Del Observatorio de Salud P?blica de Santander, , 2009. . Acesso em: 25 maio. 2020 HOEKSTRA, W. J. et al. Clinical Candidate VT-1161?s Antiparasitic Effect In Vitro, Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi. 2016. HOLT, F.; GILLAM, S. J.; NGONDI, J. M. Improving Access to Medicines for Neglected Tropical Diseases in Developing Countries: Lessons from Three Emerging Economies. PLoS Neglected Tropical Diseases, v. 6, n. 2, p. e1390, 28 fev. 2012. HOTEZ, P. J.; PECOUL, B. ?Manifesto? for Advancing the Control and Elimination of Neglected Tropical Diseases. PLoS Neglected Tropical Diseases, v. 4, n. 5, maio 2010. HOUWELING, T. A. J. et al. Socioeconomic Inequalities in Neglected Tropical Diseases: A Systematic ReviewPLoS Neglected Tropical DiseasesPublic Library of Science, , 2016. . Acesso em: 16 abr. 2020 HOWARD, E. J. et al. Frequency of the congenital transmission of Trypanosoma cruzi: A systematic review and meta-analysisBJOG: An International Journal of Obstetrics and GynaecologyNIH Public Access, , jan. 2014. . Acesso em: 6 maio. 2020 HU, Y. et al. A Review of Recent Advances and Research on Drug Target Identification Methods. Current Drug Metabolism, v. 20, n. 3, p. 209?216, 25 set. 2018. JACKSON, Y. et al. Tolerance and safety of nifurtimox in patients with chronic chagas disease. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, v. 51, n. 10, 15 nov. 2010. JONES, G. et al. Development and validation of a genetic algorithm for flexible docking. Journal of Molecular Biology, v. 267, n. 3, p. 727?748, 4 abr. 1997. JUNQUEIRA, A. C. V. et al. Manual de Capacita??o na Detec??o de Trypanosoma cruzi para Microscopistas de Mal?ria e Laboratoristas da Rede P?blica (J. R. Coura, Ed.)Rio de Janeiro, 2011. KADISH, K. M.; SMITH, K. M.; GUILARD, R. The porphyrin handbook: Phthalocyanines: Spectroscopic and electrochemical characterization. The Porphyrin Handbook: Phthalocyanines: Spectroscopic and Electrochemical Characterization, v. 16, p. 1?288, 2 dez. 2012. KAWASAKI, Y.; FREIRE, E. Finding a better path to drug selectivityDrug Discovery TodayDrug Discov Today, , nov. 2011. Dispon?vel em: <https://pubmed.ncbi.nlm.nih.gov/21839183/>. Acesso em: 1 set. 2020 KHAMIS, M. A.; GOMAA, W.; AHMED, W. F. Machine learning in computational dockingArtificial Intelligence in MedicineElsevier, , 1 mar. 2015. Dispon?vel em: <https://linkinghub.elsevier.com/retrieve/pii/S0933365715000032>. Acesso em: 4 abr. 2021 KHAN, I. et al. Synthesis, antioxidant activities and urease inhibition of some new 1,2,4-triazole and 1,3,4-thiadiazole derivatives. European journal of medicinal chemistry, v. 45, n. 11, p. 5200?5207, nov. 2010. KIRTON, S. B. et al. Prediction of binding modes for ligands in the cytochromes P450 and other heme-containing proteins. Proteins: Structure, Function, and Bioinformatics, v. 58, n. 4, p. 836?844, 1 mar. 2005. KITCHEN, D. B. et al. Docking and scoring in virtual screening for drug discovery: methods and applications. Nature Reviews Drug Discovery, v. 3, n. 11, p. 935?949, nov. 2004. KORB, O.; ST?TZLE, T.; EXNER, T. E. Empirical scoring functions for advanced Protein-Ligand docking with PLANTS. Journal of Chemical Information and Modeling, v. 49, n. 1, p. 84?96, jan. 2009. KRAUTH-SIEGEL, R. L.; COMINI, M. A. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolismBiochimica et Biophysica Acta - General Subjects, nov. 2008. . Acesso em: 17 maio. 2021 KUPWADE, R. V. et al. Catalyst-free oxidation of sulfides to sulfoxides and diethylamine catalyzed oxidation of sulfides to sulfones using Oxone as an oxidant. Research on Chemical Intermediates 2017 43:12, v. 43, n. 12, p. 6875?6888, 7 jul. 2017. LARANJA, F. S. et al. Chagas? Disease A Clinical, Epidemiologic, and Pathologic Study, 2009. Dispon?vel em: <http://ahajournals.org>. Acesso em: 9 jun. 2020 LAZARDI, K.; URBINA, J. A.; DE SOUZA, W. Ultrastructural alterations induced by two ergosterol biosynthesis inhibitors, ketoconazole and terbinafine, on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi. Antimicrobial Agents and Chemotherapy, v. 34, n. 11, p. 2097?2105, 1990. LEONARD, N. J.; JOHNSON, C. R. Periodate Oxidation of Sulfides to Sulfoxides. Scope of the Reaction. Journal of Organic Chemistry, v. 27, n. 1, p. 282?284, 1 jan. 2002. LEPESHEVA, G. I. et al. Crystal structures of Trypanosoma brucei sterol 14?- demethylase and implications for selective treatment of human infections. Journal of Biological Chemistry, v. 285, n. 3, p. 1773?1780, 15 jan. 2010. LEPESHEVA, G. I. et al. VFV as a new effective CYP51 structure-derived drug candidate for chagas disease and visceral leishmaniasis. Journal of Infectious Diseases, v. 212, n. 9, p. 1439?1448, 1 nov. 2015. LEPESHEVA, G. I.; FRIGGERI, L.; WATERMAN, M. R. CYP51 as drug targets for fungi and protozoan parasites: past, present and future. Parasitology, v. 145, n. 14, p. 1820?1836, 1 dez. 2018. LEPESHEVA, G. I.; VILLALTA, F.; WATERMAN, M. R. Targeting Trypanosoma cruzi Sterol 14?-Demethylase (CYP51). In: Advances in Parasitology. [s.l.] Academic Press, 2011. v. 75p. 65?87. LEVINE, N. D. ET AL. A newly revised classification of the Protozoa. J. Protozool., v. 27, p. 37?58, 1980. LI, J.; FU, A.; ZHANG, L. An Overview of Scoring Functions Used for Protein? Ligand Interactions in Molecular DockingInterdisciplinary Sciences: Computational Life SciencesSpringer Berlin Heidelberg, , 1 jun. 2019. Dispon?vel em: <https://doi.org/10.1007/s12539-019-00327-w>. Acesso em: 22 abr. 2021 LI, L. et al. On the dielectric ?constant? of proteins: Smooth dielectric function for macromolecular modeling and its implementation in DelPhi. Journal of Chemical Theory and Computation, v. 9, n. 4, p. 2126?2136, 9 abr. 2013. LINDEN, R. Algoritmos Gen?ticos: Uma importante ferramenta da intelig?ncia computacional. Rio de Janeiro: Editora Brasport, 2006. LUQUETTI, A. O. et al. Congenital transmission of Trypanosoma cruzi in central Brazil. A study of 1,211 individuals born to infected mothers. Mem?rias do Instituto Oswaldo Cruz, v. 110, n. 3, p. 369?376, 14 mar. 2015. MACRAE, C. F. et al. Mercury CSD 2.0 ? new features for the visualization and investigation of crystal structures. Journal of Applied Crystallography, v. 41, n. 2, p. 466? 470, 1 abr. 2008. MANJULA, P. S. et al. The crystal structures of three 3-methyl-1H-1,2,4-triazole-5- thiones, including a second polymorph of 4-[(E)-(5-bromo-2-hydroxybenzylidene)amino]- 3-methyl-1H-1,2,4-triazole-5(4H)-thione and a redetermination of 4-amino-3-methyl-1H- 1,2,4-triazole-5(4H)-thione. Acta Crystallographica Section E: Crystallographic Communications, v. 71, p. 1003?1009, 2015. MARCH, J. Advanced Organic Chemistry-Reactions: Mecanism and Structure. 3a ed. ed. [s.l.] John Willley& Sons, 1985. MARTIN, M. B. et al. Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: A potential route to chemotherapy. Journal of Medicinal Chemistry, v. 44, n. 6, p. 909?916, 15 mar. 2001. MAVROVA, A. T. et al. Synthesis, cytotoxicity and effects of some 1,2,4-triazole and 1,3,4-thiadiazole derivatives on immunocompetent cells. European journal of medicinal chemistry, v. 44, n. 1, p. 63?69, jan. 2009. MAYA, J. D. et al. Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, v. 146, n. 4, p. 601?620, abr. 2007. MOOIJ, W. T. M.; VERDONK, M. L. General and targeted statistical potentials for protein-ligand interactions. Proteins: Structure, Function and Genetics, v. 61, n. 2, p. 272?287, 1 nov. 2005. MORGON, N. H.; COUTINHO, K. M?todos de qu?mica te?rica e modelagem molecular. 1. ed. S?o Paulo: Editora e Livraria da F?sica, 2007. MORILLO, C. A. et al. Benznidazole and Posaconazole in Eliminating Parasites in Asymptomatic T. Cruzi Carriers: The STOP-CHAGAS Trial. Journal of the American College of Cardiology, v. 69, n. 8, p. 939?947, 28 fev. 2017. MORRIS, G. M. et al. Automated docking using a Lamarckian Genetic Algorithm and an empirical binding free energy function. J. Comp. Chem, v. 19, p. 1639?1662, 1998. MURCIA, L. et al. Risk Factors and Primary Prevention of Congenital Chagas Disease in a Nonendemic Country. Clinical Infectious Diseases, v. 56, n. 4, p. 496?502, 15 fev. 2013. NAVEENA, C. S.; BOJA, P.; KUMARI, N. S. Synthesis, characterization and antimicrobial activity of some disubstituted 1,3,4-oxadiazoles carrying 2- (aryloxymethyl)phenyl moiety. European journal of medicinal chemistry, v. 45, n. 11, p. 4708?19, nov. 2010. N?BREGA, A. A. et al. Oral transmission of chagas disease by consumption of A?a? palm fruit, Brazil. Emerging Infectious Diseases, v. 15, n. 4, p. 653?655, abr. 2009. NOTREDAME, C.; HIGGINS, D. G.; HERINGA, J. T-coffee: A novel method for fast and accurate multiple sequence alignment. Journal of Molecular Biology, v. 302, n. 1, p. 205?217, 8 set. 2000. N??EZ-VERGARA, L. J. et al. Nitro radical anion formation from nifurtimox. Part 1: Biological evidences in Trypanosoma cruzi. Bioelectrochemistry and Bioenergetics, v. 43, n. 1, p. 151?155, 1 jun. 1997. OLIVEIRA, F. G. et al. Molecular docking study and development of an empirical binding free energy model for phosphodiesterase 4 inhibitors. Bioorganic & medicinal chemistry, v. 14, n. 17, p. 6001?11, 1 set. 2006. OPERA, T. I. Chemoinformatics in drug discovery. [s.l.] Weinheim: Wiley-VCH, 2005. OSORIO-M?NDEZ, J. F.; CEVALLOS, A. M. Discovery and genetic validation of chemotherapeutic targets for Chagas? diseaseFrontiers in Cellular and Infection MicrobiologyFrontiers Media S.A., , 7 jan. 2019. Dispon?vel em: <https://www.rcsb.>. Acesso em: 7 set. 2020 PAHO/WHO - Chagas Disease. Dispon?vel em: <https://www.paho.org/hq/index.php?option=com_content&view=category&layout=blog &id=3591&Itemid=3921&lang=en>. Acesso em: 1 abr. 2020. PAN AMERICAN HEALTH ORGANIZATION. Guidelines for the diagnosis and treatment of Chagas diseaseWashington, D.C, 2019. Dispon?vel em: <https://iris.paho.org/handle/10665.2/49653> PATTERSON, S. et al. Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: Discovery, synthesis, and characterization of their binding mode by protein crystallography. Journal of Medicinal Chemistry, v. 54, n. 19, p. 6514?6530, 13 out. 2011. PEREIRA, I. R. et al. A human type 5 adenovirus-based Trypanosoma cruzi therapeutic vaccine re-programs immune response and reverses chronic cardiomyopathy. PLoS pathogens, v. 11, n. 1, p. 1?26, 2015. P?REZ-AYALA, A. et al. Gastro-intestinal Chagas disease in migrants to Spain: Prevalence and methods for early diagnosis. Annals of Tropical Medicine and Parasitology, v. 105, n. 1, p. 25?29, jan. 2011. P?REZ-MOLINA, J. A.; MOLINA, I. Chagas disease. The Lancet, v. 391, n. 10115, p. 82?94, 2018. PETRAGLIA KROPF, S.; MASSARANI, L. Carlos Chagas, A ci?ncia para combater doen?as tropicais. p. 16, 2009. PINTO, A. Y. D. N. et al. Fase aguda da doen?a de Chagas na Amaz?nia brasileira. Estudo de 233 casos do Par?, Amap? e Maranh?o observados entre 1988 e 2005. Revista da Sociedade Brasileira de Medicina Tropical, v. 41, n. 6, p. 602?614, nov. 2008. PINTO DIAS, J. C. The indeterminate form of human chronic Chagas? disease. A clinical epidemiological reviewRevista da Sociedade Brasileira de Medicina TropicalSBMT, , 1989. . Acesso em: 9 jun. 2020 PODUST, L. M. et al. Estriol Bound and Ligand-free Structures of Sterol 14?- Demethylase. Structure, v. 12, n. 11, p. 1937?1945, nov. 2004. PODUST, L. M.; POULOS, T. L.; WATERMAN, M. R. Crystal structure of cytochrome P450 14?-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. v. 98, n. 6, 13 mar. 2001a. PODUST, L. M.; POULOS, T. L.; WATERMAN, M. R. Crystal structure of cytochrome P450 14alpha -sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proceedings of the National Academy of Sciences of the United States of America, v. 98, n. 6, p. 3068?73, 13 mar. 2001b. POLLACK, L. Historical Series: National Lecture. [s.l: s.n.]. Dispon?vel em: <https://www.ks.uiuc.edu/events/NationalLecture2015/reflection/>. Acesso em: 28 nov. 2021. POOLE, L. B. The basics of thiols and cysteines in redox biology and chemistryFree Radical Biology and MedicineElsevier Inc., , 2015. Dispon?vel em: <https://pubmed.ncbi.nlm.nih.gov/25433365/>. Acesso em: 12 set. 2020 PRATA, A. et al. Tratamento da Doen?a de Chagas pelo Nifurtimox (Bayer 2502). Revista da Sociedade Brasileira de Medicina Tropical, v. 9, n. 6, p. 297?307, dez. 1975. PREVIATO, L. Macromol?culas: Carboidratos de superf?cie do Trypanosoma cruzi. Dispon?vel em: <http://chagas.fiocruz.br/bioquimica/>. Acesso em: 10 set. 2020. PRIETO-MART?NEZ, F. D. et al. Computational Drug Design Methods?Current and Future Perspectives. In: In Silico Drug Design. [s.l.] Elsevier, 2019. p. 19?44. RASSI, A.; RASSI, A.; MARIN-NETO, J. A. Chagas diseaseThe LancetElsevier, , 17 abr. 2010. . Acesso em: 7 jun. 2020 RIBEIRO, T. S. et al. Toxic effects of natural piperine and its derivatives on epimastigotes and amastigotes of Trypanosoma cruzi. Bioorganic & Medicinal Chemistry Letters, v. 14, n. 13, p. 3555?3558, 5 jul. 2004. RILEY, J. et al. Development of a Fluorescence-based Trypanosoma cruzi CYP51 Inhibition Assay for Effective Compound Triaging in Drug Discovery Programmes for Chagas Disease. PLoS Neglected Tropical Diseases, v. 9, n. 9, p. 1?12, 2015. ROCHA JR., J. G. Desenvolvimento de um modelo emp?rico de prediss?o de atividade de inibidores da esterol 14alfa-desmetilase (CYP51) utilizando o m?todo semi-emp?rico PM6. UFRRJ: [s.n.]. ROCHA, S. F. L. DA S. Desenvolvimento de um Modelo Emp?rico de Predi??o da Atividade de Inibidores da Urease utilizando o M?todo Semi-Emp?rico PM6. [s.l: s.n.]. ROCHA, S. F. L. DA S. Desenvolvimento de um modelo emp?rico de predi??o da seletividade e da atividade de inibidores da Shp2 utilizando o m?todo semi-emp?rico PM7. Serop?dica: Universidade Federal Rural do Rio de Janeiro, 29 jan. 2019. SALD?VAR-GONZ?LEZ, F.; PRIETO-MART?NEZ, F. D.; MEDINA-FRANCO, J. L. Descubrimiento y desarrollo de f?rmacos: un enfoque computacional. Educacion Quimica, v. 28, n. 1, p. 51?58, 1 jan. 2017. SANT?ANNA; C. M. R. M?todos de modelagem molecular para estudo e planejamento de compostos bioativos: Uma introdu??o. Rev. Virtual Qu?m, v. 1, p. 49?57, 2009. SANTANNA, C. M. R. M?todos de modelagem molecular para estudo e planejamento de compostos bioativos : Uma introdu??o Resumo M?todos de modelagem molecular para estudo e planejamento de compostos bioativos : Uma introdu??o. Rev. Virtual Quim., v. 1, n. 1, p. 49?57, 2009. SCHMUNIS, G. A. Epidemiology of Chagas disease in non-endemic countries: The role of international migration. Memorias do Instituto Oswaldo Cruz. Anais...Funda??o Oswaldo Cruz, out. 2007. . Acesso em: 5 maio. 2020 SCOTTI, L. et al. Modelagem molecular aplicada ao desenvolvimento de mol?culas com atividade antioxidante visando ao uso cosm?tico. Revista Brasileira de Ci?ncias Farmac?uticas, v. 43, n. 2, p. 153?166, 2007. SHELDRICK, G. M. A short history of SHELXActa Crystallographica Section A: Foundations of CrystallographyInternational Union of Crystallography, , 1 jan. 2008. Acesso em: 31 mar. 2020 SHYADEHI, A. Z. et al. The mechanism of the acyl-carbon bond cleavage reaction catalyzed by recombinant sterol 14 alpha-demethylase of Candida albicans (other names are: lanosterol 14 alpha-demethylase, P-45014DM, and CYP51). The Journal of biological chemistry, v. 271, n. 21, p. 12445?12450, 1996. SIES, H.; BERNDT, C.; JONES, D. P. Oxidative Stress. Annual Review of Biochemistry, v. 86, n. 1, p. 715?748, 20 jun. 2017. SOSA, E. J. et al. Target-Pathogen: A structural bioinformatic approach to prioritize drug targets in pathogens. Nucleic Acids Research, v. 46, n. D1, p. D413?D418, 1 jan. 2018. SPINKS, D. et al. Design, synthesis and biological evaluation of Trypanosoma brucei Trypanothione Synthetase inhibitors. ChemMedChem, v. 7, n. 1, p. 95?106, 2 jan. 2012. STEINDEL, M. et al. Characterization of Trypanosoma cruzi isolated from humans, vectors, and animal reservoirs following an outbreak of acute human Chagas disease in Santa Catarina State, Brazil. Diagnostic Microbiology and Infectious Disease, v. 60, n. 1, p. 25?32, jan. 2008. STEWART, J. J. P. Optimization of parameters for semiempirical methods I. Method. Journal of Computational Chemistry, v. 10, n. 2, p. 209?220, 1 mar. 1989. STEWART, J. J. P. MOPAC 2000.00 Manual.Tokyo, JapanFujitsu Limited, , 1999. STEWART, J. J. P. Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements. Journal of molecular modeling, v. 13, n. 12, p. 1173?213, 2007. STEWART, J. J. P. Optimization of parameters for semiempirical methods VI: More modifications to the NDDO approximations and re-optimization of parameters. Journal of Molecular Modeling, v. 19, n. 1, p. 1?32, 2013a. STEWART, J. J. P. Optimization of parameters for semiempirical methods VI: More modifications to the NDDO approximations and re-optimization of parameters. Journal of Molecular Modeling, v. 19, n. 1, p. 1?32, jan. 2013b. THIEL, W. Semiempirical quantum?chemical methods. Wiley Interdisciplinary Reviews: Computational Molecular Science, v. 4, n. 2, p. 145?157, 1 mar. 2014. THIEL, W.VOITYUK, A. A. Extension of the MNDO formalism to d-orbitals - Integral approximations and preliminary numerical results. Theor. Chim. Acta, v. 81, p. 391?404, 1992. TROST, B. M.; CURRAN, D. P. Chemoselective oxidation of sulfides to sulfones with potassium hydrogen persulfate. Tetrahedron Letters, v. 22, n. 14, p. 1287?1290, 1 jan. 1981. TURNOCK, D. C.; FERGUSON, M. A. Sugar nucleotide pools of Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major. Eukaryotic cell, v. 6, n. 8, p. 1450? 1463, ago. 2007. URBINA, J. A. et al. In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy, v. 48, n. 7, p. 2379?2387, 1 jul. 2004. VALENTE, S. A. DA S. et al. Analysis of an acute Chagas disease outbreak in the Brazilian Amazon: human cases, triatomines, reservoir mammals and parasites. Transactions of the Royal Society of Tropical Medicine and Hygiene, v. 103, n. 3, p. 291?297, mar. 2009. VERDONK, M. L. et al. Improved protein-ligand docking using GOLD. Proteins, v. 52, n. 4, p. 609?623, 1 set. 2003. VILLALTA, F.; RACHAKONDA, G. Advances in preclinical approaches to Chagas disease drug discovery. Expert Opinion on Drug Discovery, v. 14, n. 11, p. 1161?1174, 2 nov. 2019. WANG, S. et al. Protein kinase C. Modeling of the binding site and prediction of binding constants. Journal of medicinal chemistry, v. 37, n. 9, p. 1326?38, 29 abr. 1994. WHO. World Health Organization. Global plan to combat neglected tropical diseases 2008?2015. Dispon?vel em: <http://apps.who.int/iris/bitstream/handle/10665/69708/%0AWHO_CDS_NTD_2007.3_en g.pdf?sequence=1>. Acesso em: 7 out. 2019. WOO, H.-M. et al. Active spice-derived components can inhibit inflammatory responses of adipose tissue in obesity by suppressing inflammatory actions of macrophages and release of monocyte chemoattractant protein-1 from adipocytes. Life sciences, v. 80, n. 10, p. 926?931, 13 fev. 2007. WORLD HEALTH ORGANISATION. WHO Technical Report Series 905. Control of Chagas disease: second report of the WHO expert Committee. Geneva: [s.n.]. Dispon?vel em: <https://apps.who.int/iris/bitstream/handle/10665/42443/WHO_TRS_905.pdf?sequence=1 &isAllowed=y>. Acesso em: 15 abr. 2020. YOSHIDA, Y. et al. Sterol 14-demethylase P450 (CYP51) provides a breakthrough for the discussion on the evolution of cytochrome P450 gene superfamily. Biochemical and biophysical research communications, v. 273, n. 3, p. 799?804, 14 jul. 2000. YUNG-CHI, C.; PRUSOFF, W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochemical pharmacology, v. 22, n. 23, p. 3099?3108, 1 dez. 1973. ZINGALES, B. et al. The revised Trypanosoma cruzi subspecific nomenclature: Rationale, epidemiological relevance and research applicationsInfection, Genetics and Evolution, mar. 2012. . Acesso em: 15 abr. 2020Doen?a de Chagastriaz?isesterol 14?-desmetilasesemi-emp?ricodocagem molecularChagas diseasetriazolessterol 14?-demethylasesemiempirical methodmolecular dockingQu?micaDesenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitroDevelopment of triazoles piperine derivatives inhibitors of Trypanosoma cruzi's CYP51: optimization of a prediction model of theoretical activity, synthesis and in vitro activityinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFRRJinstname:Universidade Federal Rural do Rio de Janeiro (UFRRJ)instacron:UFRRJTHUMBNAIL2021 - Larissa Henriques Evangelista Castro.pdf.jpg2021 - Larissa Henriques Evangelista Castro.pdf.jpgimage/jpeg3482http://localhost:8080/tede/bitstream/jspui/6553/4/2021+-+Larissa+Henriques+Evangelista+Castro.pdf.jpgf29c2b45d33767a673000ca1f6da4c3bMD54TEXT2021 - Larissa Henriques Evangelista Castro.pdf.txt2021 - Larissa Henriques Evangelista Castro.pdf.txttext/plain283627http://localhost:8080/tede/bitstream/jspui/6553/3/2021+-+Larissa+Henriques+Evangelista+Castro.pdf.txt4f9150ac64d28261cdaec5edfbee6cb3MD53ORIGINAL2021 - Larissa Henriques Evangelista Castro.pdf2021 - Larissa Henriques Evangelista Castro.pdfapplication/pdf7382938http://localhost:8080/tede/bitstream/jspui/6553/2/2021+-+Larissa+Henriques+Evangelista+Castro.pdf0f6d9dd3eab2a65b6e1d58680ba9fbbaMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82089http://localhost:8080/tede/bitstream/jspui/6553/1/license.txt7b5ba3d2445355f386edab96125d42b7MD51jspui/65532023-05-03 01:00:29.747oai:localhost: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Biblioteca Digital de Teses e Dissertaçõeshttps://tede.ufrrj.br/PUBhttps://tede.ufrrj.br/oai/requestbibliot@ufrrj.br||bibliot@ufrrj.bropendoar:2023-05-03T04:00:29Biblioteca Digital de Teses e Dissertações da UFRRJ - Universidade Federal Rural do Rio de Janeiro (UFRRJ)false
dc.title.por.fl_str_mv Desenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitro
dc.title.alternative.eng.fl_str_mv Development of triazoles piperine derivatives inhibitors of Trypanosoma cruzi's CYP51: optimization of a prediction model of theoretical activity, synthesis and in vitro activity
title Desenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitro
spellingShingle Desenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitro
Castro, Larissa Henriques Evangelista
Doen?a de Chagas
triaz?is
esterol 14?-desmetilase
semi-emp?rico
docagem molecular
Chagas disease
triazoles
sterol 14?-demethylase
semiempirical method
molecular docking
Qu?mica
title_short Desenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitro
title_full Desenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitro
title_fullStr Desenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitro
title_full_unstemmed Desenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitro
title_sort Desenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitro
author Castro, Larissa Henriques Evangelista
author_facet Castro, Larissa Henriques Evangelista
author_role author
dc.contributor.advisor1.fl_str_mv Sant?Anna, Carlos Mauricio Rabello de
dc.contributor.advisor1ID.fl_str_mv 827.232.227-72
dc.contributor.advisor-co1.fl_str_mv Lima, Marco Edilson Freire de
dc.contributor.advisor-co2.fl_str_mv Ifa, Demian Rocha
dc.contributor.referee1.fl_str_mv Sant' Anna, Carlos Maur?cio Rabello de
dc.contributor.referee2.fl_str_mv Lima, Aurea Echevarria Aznar Neves
dc.contributor.referee3.fl_str_mv Graebin, Cedric Stephan
dc.contributor.referee4.fl_str_mv Trossini, Gustavo Henrique Goulart
dc.contributor.referee5.fl_str_mv Rodrigues, Daniel Alencar
dc.contributor.authorID.fl_str_mv 142.560.187-19
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/2174763588443208
dc.contributor.author.fl_str_mv Castro, Larissa Henriques Evangelista
contributor_str_mv Sant?Anna, Carlos Mauricio Rabello de
Lima, Marco Edilson Freire de
Ifa, Demian Rocha
Sant' Anna, Carlos Maur?cio Rabello de
Lima, Aurea Echevarria Aznar Neves
Graebin, Cedric Stephan
Trossini, Gustavo Henrique Goulart
Rodrigues, Daniel Alencar
dc.subject.por.fl_str_mv Doen?a de Chagas
triaz?is
esterol 14?-desmetilase
semi-emp?rico
docagem molecular
topic Doen?a de Chagas
triaz?is
esterol 14?-desmetilase
semi-emp?rico
docagem molecular
Chagas disease
triazoles
sterol 14?-demethylase
semiempirical method
molecular docking
Qu?mica
dc.subject.eng.fl_str_mv Chagas disease
triazoles
sterol 14?-demethylase
semiempirical method
molecular docking
dc.subject.cnpq.fl_str_mv Qu?mica
description Chagas disease (CD) is a neglected tropical disease caused by the parasite Trypanosoma cruzi and presents millions of cases in several countries. Currently there are no vaccines for CD prevention and there are only two drugs for its treatment, but in Brazil, only benzonidazole is used and is ineffective on disease?s chronic phase. Thus, research for new drugs becomes essential. The enzyme sterol 14?-desmethylase (CYP51) belongs to the ergosterol biosynthesis pathway, which are fundamental for the integrity of the T. cruzi?s cell membrane. Its inhibition causes the parasite?s death and it can be promoted by the coordination of heterocyclic compounds with the iron atom of the enzyme?s heme group. On a previous work, a theoretical model of activity prediction for new inhibitors of CYP51 (T. cruzi), based on experimental and theoretical parameters calculated by molecular modeling, which was used for design new triazole piperine derivatives. On this current work, the original theoretical model was optimized using the semi-empirical PM7 method instead of PM6 and a selectivity study was done by molecular docking of heterocyclic compounds in T. cruzi?s CYP51 and H. sapiens?s CYP51. The most promising compounds, planned by the original model, were synthesized, evaluated in vitro against T. cruzi and they were tested for CYP51 inhibition. The new model presented a multiple correlation coefficient slightly higher than the original. The docking study indicates a likely selectivity of the compounds for the parasite?s enzyme. The compounds showed activities against trypomastigote forms, in agreement with the general predictions made by the model, and low cytotoxicity in primate cells. Preliminary enzyme inhibition assays indicated that the compounds designed with the model are in fact capable of inhibiting the parasite's CYP51.
publishDate 2021
dc.date.issued.fl_str_mv 2021-12-16
dc.date.accessioned.fl_str_mv 2023-05-02T21:27:15Z
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 CASTRO, Larissa Henriques Evangelista. Desenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitro. 2021. 175 p. Tese (Doutorado em Qu?mica, Qu?mica Org?nica) - Instituto de Qu?mica, Universidade Federal Rural do Rio de Janeiro. Serop?dica, RJ, 2021.
dc.identifier.uri.fl_str_mv https://tede.ufrrj.br/jspui/handle/jspui/6553
identifier_str_mv CASTRO, Larissa Henriques Evangelista. Desenvolvimento de tyriaz?is derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimiza??o de um modelo de previs?o de atividade te?rica, s?ntese e atividade in vitro. 2021. 175 p. Tese (Doutorado em Qu?mica, Qu?mica Org?nica) - Instituto de Qu?mica, Universidade Federal Rural do Rio de Janeiro. Serop?dica, RJ, 2021.
url https://tede.ufrrj.br/jspui/handle/jspui/6553
dc.language.iso.fl_str_mv por
language por
dc.relation.references.por.fl_str_mv ALARC?N DE NOYA, B. et al. Large Urban Outbreak of Orally Acquired Acute Chagas Disease at a School in Caracas, Venezuela. The Journal of Infectious Diseases, v. 201, n. 9, p. 1308?1315, maio 2010. ALC?CER, L. Introdu??o ? qu?mica qu?ntica computacional. Rio de Janeiro: IST Press, Lisboa, 2007. AMINPOUR, M.; MONTEMAGNO, C.; TUSZYNSKI, J. A. An Overview of Molecular Modeling for Drug Discovery with Specific Illustrative Examples of Applications. Molecules, v. 24, n. 9, 2019. ANDRIANI, G. et al. Antitrypanosomal lead discovery: Identification of a ligandefficient inhibitor of Trypanosoma cruzi CYP51 and parasite growth. Journal of Medicinal Chemistry, v. 56, n. 6, p. 2556?2567, 2013. BARRY, M. A. et al. A therapeutic nanoparticle vaccine against Trypanosoma cruzi in a BALB/c mouse model of Chagas disease. Human vaccines & immunotherapeutics, v. 12, n. 4, p. 976?987, 2 abr. 2016. BASTOS, C. J. C. et al. Clinical outcomes of thirteen patients with acute chagas disease acquired through oral transmission from two urban outbreaks in Northeastern Brazil. PLoS Neglected Tropical Diseases, v. 4, n. 6, jun. 2010. BELL, L. et al. Evaluation of fluorescence- and mass spectrometry-based CYP inhibition assays for use in drug discovery. Journal of Biomolecular Screening, v. 13, n. 5, p. 343?353, 2008. BEN?TEZ, D. et al. Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids. PLoS Neglected Tropical Diseases, v. 10, n. 4, 12 abr. 2016. BERN, C. et al. Evaluation and treatment of chagas disease in the United States: A systematic reviewJournal of the American Medical AssociationJAMA, , 14 nov. 2007. Dispon?vel em: <https://pubmed.ncbi.nlm.nih.gov/18000201/>. Acesso em: 1 set. 2020 BOIANI, M. et al. Mode of action of Nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi: Is oxidative stress involved? Biochemical Pharmacology, v. 79, n. 12, p. 1736?1745, 15 jun. 2010. BRONOWSKA, A. K. Thermodynamics of Ligand-Protein Interactions: Implications for Molecular Design. Thermodynamics - Interaction Studies - Solids, Liquids and Gases, 2 nov. 2011. BROOIJMANS, N.; KUNTZ, I. D. Molecular Recognition and Docking Algorithms. Annual Review of Biophysics and Biomolecular Structure, v. 32, n. 1, p. 335?373, 28 jun. 2003. Bruker, APEX2 and SAINT Programs for Data Reduction, APEX2, SAINT and SADABS. (2013) Bruker AXS Inc., Madison, Wisconsin, USA. , 2013. Bruker, APEX2, SAINT and SADABS, APEX II. (2009) Bruker AXS Inc., Madison, Wisconsin, USA. , 2009. CALDAS, I. S.; SANTOS, E. G.; NOVAES, R. D. An evaluation of benznidazole as a Chagas disease therapeutic. https://doi.org/10.1080/14656566.2019.1650915, v. 20, n. 15, p. 1797?1807, 13 out. 2019. CANSIZ, A. et al. 4-Allyl-5-pyridin-4-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione: Synthesis, experimental and theoretical characterization. Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, v. 91, p. 136?145, jun. 2012. CASBARRA, L.; PROCACCI, P. Binding free energy predictions in host-guest systems using Autodock4. A retrospective analysis on SAMPL6, SAMPL7 and SAMPL8 challenges. Journal of Computer-Aided Molecular Design, v. 35, n. 6, p. 721?729, 1 jun. 2021. CASTRO, L. H. E. Constru??o de um Modelo de Previs?o de Atividade para o Planejamento e S?ntese de Triaz?is Promissores para Inibi??o da CYP51 de Trypanosoma cruzi.Disserta??o (Mestrado em Qu?mica) Serop?dica, 2016. CERECETTO, H.; GONZ?LEZ, M. Antiparasitic prodrug nifurtimox: revisiting its activation mechanism. Future microbiology, v. 6, n. 8, p. 847?850, 23 ago. 2011. CHAGAS, C. J. R. Nova entidade m?rbida do homem. Resumo geral de estudos etiol?jicos e cl?nicos. Mem?rias do Instituto Oswaldo, p. 219?275, 1909. CHAMBERS, C. C. et al. Model for aqueous solvation based on class IV atomic charges and first solvation shell effects. Journal of Physical Chemistry, v. 100, n. 40, p. 16385?16398, 3 out. 1996. CHATELAIN, E. Chagas disease drug discovery: Toward a new eraJournal of Biomolecular ScreeningSAGE Publications Inc., , 30 jan. 2015. Dispon?vel em: <https://pubmed.ncbi.nlm.nih.gov/25245987/>. Acesso em: 1 set. 2020 CHEN, C.-K. et al. Structural Characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei Bound to the Antifungal Drugs Posaconazole and Fluconazole. PLoS Neglected Tropical Diseases, v. 4, n. 4, p. e651, 6 abr. 2010. CHEN, H.-S.; MENG, H.-H.; CHENG, K.-C. A survey of methods used for the identification and characterization of inks. Forensic Science Journal, v. 1, n. 1, p. 1?14, 2002. CHRISTENSEN, A. S. et al. Semiempirical Quantum Mechanical Methods for Noncovalent Interactions for Chemical and Biochemical Applications. Chemical Reviews, v. 116, n. 9, p. 5301?5337, 11 maio 2016. CLAYDEN, J.; GREEVES, N.; WARREN, S. Organic Chemistry. 2nd. ed. [s.l.] Oxford University Press (OUP), 2012. COLODETTE, N. M. et al. Novel phosphatidylinositol 4-kinases III beta (PI4KIII?) inhibitors discovered by virtual screening using free energy models. Journal of Computer- Aided Molecular Design, v. 34, n. 10, p. 1091?1103, 1 out. 2020. CONTEH, L.; ENGELS, T.; MOLYNEUX, D. H. Socioeconomic aspects of neglected tropical diseases. Lancet (London, England), v. 375, n. 9710, p. 239?247, 2010. CORT?S-RUIZ, E. M. et al. Computational Methods to Discover Compounds for the Treatment of Chagas Disease. In: Advances in Protein Chemistry and Structural Biology. [s.l.] Academic Press Inc., 2018. v. 113p. 119?142. COURA, J. R. Transmission of chagasic infection by oral route in the natural history of Chagas disease. Rev Soc Bras Med Trop, v. 39 (Supl., p. 113?117, 2006. COURA, J. R. Chagas disease: What is known and what is needed - A background article. Memorias do Instituto Oswaldo Cruz. Anais...Fundacao Oswaldo Cruz, 2007. . Acesso em: 5 maio. 2020 COURA, J. R. The main sceneries of chagas disease transmission. The vectors, blood and oral transmissions - A comprehensive review. Memorias do Instituto Oswaldo Cruz, v. 110, n. 3, p. 277?282, 2015. COURA, J. R.; BORGES-PEREIRA, J. Chronic phase of Chagas disease: Why should it be treated? A comprehensive reviewMemorias do Instituto Oswaldo CruzFundacao Oswaldo Cruz, , 2011. Dispon?vel em: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074- 02762011000600001&lng=en&nrm=iso&tlng=en>. Acesso em: 1 set. 2020 COURA, J. R.; CASTRO, S. L. DE. A Critical Review on Chagas Disease Chemotherapy. Mem?rias do Instituto Oswaldo Cruz, v. 97, n. 1, p. 3?24, jan. 2002. COURA, J. R.; DIAS, J. C. P. Epidemiology, control and surveillance of Chagas disease - 100 years after its discovery. Memorias do Instituto Oswaldo Cruz, v. 104, n. SUPPL. 1, p. 31?40, 2009. COURA, J. R.; V?AS, P. A. Chagas disease: A new worldwide challengeNature, 24 jun. 2010. Dispon?vel em: <http://www.nature.com/articles/nature09221>. Acesso em: 5 maio. 2020 CRAMER, C. J.; TRUHLAR, D. G. PM3-SM3: A general parameterization for including aqueous solvation effects in the PM3 molecular orbital model. Journal of Computational Chemistry, v. 13, n. 9, p. 1089?1097, 1 nov. 1992. DA COSTA FILHO, P. A.; POPPI, R. J. Algoritmo gen?tico em qu?mica. Qu?mica Nova, v. 22, n. 3, p. 405?411, 1999. DAUCHY, F.-A. et al. Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model. PLOS Neglected Tropical Diseases, v. 10, n. 11, p. e0005125, 17 nov. 2016. DE NOYA, B. A. et al. Update on oral chagas disease outbreaks in Venezuela: Epidemiological, clinical and diagnostic approaches. Memorias do Instituto Oswaldo Cruz, v. 110, n. 3, p. 377?386, 2015. DE OLIVEIRA, C. S. et al. Synthetic Approaches and Pharmacological Activity of 1,3,4-Oxadiazoles: A Review of the Literature from 2000?2012. Molecules 2012, Vol. 17, Pages 10192-10231, v. 17, n. 9, p. 10192?10231, 27 ago. 2012. DE PAULA, V. F. et al. Synthesis and insecticidal activity of new amide derivatives of piperine. Pest Manag Sci, v. 56, p. 168?174, 2000. DE RYCKER, M. et al. Challenges and recent progress in drug discovery for tropical diseasesNatureNature Publishing Group, , 26 jul. 2018. Dispon?vel em: <https://pubmed.ncbi.nlm.nih.gov/30046073/>. Acesso em: 1 set. 2020 DE SOUZA, W.; RODRIGUES, J. C. F. Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs. Interdisciplinary Perspectives on Infectious Diseases, v. 2009, p. 1?19, 2009. DEWAR, M. J. S. et al. AM1: A New General Purpose Quantum Mechanical Molecular Model1. Journal of the American Chemical Society, v. 107, n. 13, p. 3902? 3909, 1985. DEWAR, M. J. S.; THIEL, W. Ground states of molecules. 38. The MNDO method. Approximations and parameters. J. Am. Chem. Soc., v. 99, p. 4899?4907, 1977. DIAS, J. P. et al. Acute Chagas disease outbreak associated with oral transmission. Revista da Sociedade Brasileira de Medicina Tropical, v. 41, n. 3, p. 296?300, 2008. DIMASI, J. A.; GRABOWSKI, H. G.; HANSEN, R. W. Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics, v. 47, p. 20?33, 1 maio 2016. DNDi | Symptoms, transmission, and current treatments for Chagas disease. Dispon?vel em: <https://dndi.org/diseases/chagas/facts/>. Acesso em: 5 dez. 2021. Doen?a de Chagas ? Portugu?s (Brasil). Dispon?vel em: <https://www.gov.br/saude/pt-br/assuntos/saude-de-a-a-z/d/doenca-de-chagas>. Acesso em: 5 dez. 2021. ELDRIDGE, M. D. et al. Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. Journal of Computer-Aided Molecular Design, v. 11, n. 5, p. 425?445, 1997. FAUNDEZ, M. et al. Buthionine sulfoximine increases the toxicity of nifurtimox and benznidazole to Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy, v. 49, n. 1, p. 126?130, jan. 2005. FEASEY, N. et al. Neglected tropical diseases. British medical bulletin, v. 93, n. 1, p. 179?200, mar. 2010. FERREIRA, W. S. Utiliza??o da piperina como prot?tipo na s?ntese de novos antichag?sicos da classe das 1,3,4- tiadiaz?lio-2- fenilaminidasSerop?dica, Rio de Janeiro, 2006. FERREIRA, W. S. et al. Piperine, its Analogues and Derivatives: Potencial as Antiparasitic Drugs. Revista Virtual de Qu?mica, v. 4, n. 3, p. 208?224, 2012. FRADERA, X.; BABAOGLU, K. Overview of Methods and Strategies for Conducting Virtual Small Molecule ScreeningCurrent protocols in chemical biologyCurr Protoc Chem Biol, , 14 set. 2017. Dispon?vel em: <https://pubmed.ncbi.nlm.nih.gov/28910858/>. Acesso em: 28 jun. 2021 FRAN?A, R. R. F. et al. Inibidores potentes da enzima esterol 14?-desmetilase contra Trypanosoma cruzi. Revista Virtual de Quimica, v. 6, n. 5, p. 1483?1516, 2014. FRANKLIM, T. N. et al. Design, synthesis and trypanocidal evaluation of novel 1,2,4-triazoles-3- thiones derived from natural piperine. Molecules, v. 18, n. 6, p. 6366? 6382, 2013. FRANKLIM, T. N. et al. Design, Synthesis, Trypanocidal Activity, and Studies on Human Albumin Interaction of Novel S-Alkyl-1,2,4-triazoles. Article J. Braz. Chem. Soc, v. 30, n. 7, p. 1378?1394, 2019. FRAUCHES-SANTOS, C. S?NTESE E AVALIA??O DA ATIVIDADE ANTICORROSIVA DE CLORETOS DE 1, 3, 4-TIADIAZ?LIO-2-FENILAMINAS E 1, 3, 4- TRIAZ?LIO-2-TIOLATOS EM MEIO ?CIDOSerop?dica, Rio de Janeiro, 2017. FREIRE-DE-LIMA, L. et al. The toxic effects of piperine against Trypanosoma cruzi: ultrastructural alterations and reversible blockage of cytokinesis in epimastigote forms. Parasitology Research, v. 102 (5), 2008. FRIGGERI, L. et al. Validation of Human Sterol 14?-Demethylase (CYP51) Druggability: Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors. Journal of Medicinal Chemistry, v. 62, n. 22, p. 10391?10401, 27 nov. 2019. GASCON, J.; BERN, C.; PINAZO, M.-J. Chagas disease in Spain, the United States and other non-endemic countries. Acta Tropica, v. 115, n. 1?2, p. 22?27, jul. 2010. GIULIVI, C.; TURRENS, J. F.; BOVERIS, A. Chemiluminescence enhancement by trypanocidal drugs and by inhibitors of antioxidant enzymes in Trypanosoma cruzi. Molecular and Biochemical Parasitology, v. 30, n. 3, p. 243?251, 1 set. 1988. GONZ?LEZ-MEDINA, M. et al. Open chemoinformatic resources to explore the structure, properties and chemical space of moleculesRSC AdvancesRoyal Society of Chemistry, , 21 nov. 2017. Dispon?vel em: <https://pubs.rsc.org/en/content/articlehtml/2017/ra/c7ra11831g>. Acesso em: 11 out. 2020 GROS, L. et al. New azasterols against Trypanosoma brucei: Role of 24-sterol methyltransferase in inhibitor action. Antimicrobial Agents and Chemotherapy, v. 50, n. 8, p. 2595?2601, ago. 2006. GUEDES-DA-SILVA, F. H. et al. Antitrypanosomal activity of sterol 14?- demethylase (CYP51) inhibitors VNI and VFV in the swiss mouse models of chagas disease induced by the Trypanosoma cruzi Y strain. Antimicrobial Agents and Chemotherapy, v. 61, n. 4, 1 abr. 2017. HARGROVE, T. Y. et al. A requirement for an active proton delivery network supports a compound I-mediated C???C bond cleavage in CYP51 catalysis. 2020a. HARGROVE, T. Y. et al. A requirement for an active proton delivery network supports a compound I-mediated C?C bond cleavage in CYP51 catalysis. Journal of Biological Chemistry, v. 295, n. 29, p. 9998?10007, 17 jul. 2020b. HAUBRICH, B. A. et al. Discovery of an ergosterol-signaling factor that regulates trypanosoma brucei growth. Journal of Lipid Research, v. 56, n. 2, p. 331?341, 1 fev. 2015. HERNANDEZ, L. M. et al. Brote de Chagas agudo en Lebrija, Santander 2008Revista Del Observatorio de Salud P?blica de SantanderRevista Del Observatorio de Salud P?blica de Santander, , 2009. . Acesso em: 25 maio. 2020 HOEKSTRA, W. J. et al. Clinical Candidate VT-1161?s Antiparasitic Effect In Vitro, Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi. 2016. HOLT, F.; GILLAM, S. J.; NGONDI, J. M. Improving Access to Medicines for Neglected Tropical Diseases in Developing Countries: Lessons from Three Emerging Economies. PLoS Neglected Tropical Diseases, v. 6, n. 2, p. e1390, 28 fev. 2012. HOTEZ, P. J.; PECOUL, B. ?Manifesto? for Advancing the Control and Elimination of Neglected Tropical Diseases. PLoS Neglected Tropical Diseases, v. 4, n. 5, maio 2010. HOUWELING, T. A. J. et al. Socioeconomic Inequalities in Neglected Tropical Diseases: A Systematic ReviewPLoS Neglected Tropical DiseasesPublic Library of Science, , 2016. . Acesso em: 16 abr. 2020 HOWARD, E. J. et al. Frequency of the congenital transmission of Trypanosoma cruzi: A systematic review and meta-analysisBJOG: An International Journal of Obstetrics and GynaecologyNIH Public Access, , jan. 2014. . Acesso em: 6 maio. 2020 HU, Y. et al. A Review of Recent Advances and Research on Drug Target Identification Methods. Current Drug Metabolism, v. 20, n. 3, p. 209?216, 25 set. 2018. JACKSON, Y. et al. Tolerance and safety of nifurtimox in patients with chronic chagas disease. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, v. 51, n. 10, 15 nov. 2010. JONES, G. et al. Development and validation of a genetic algorithm for flexible docking. Journal of Molecular Biology, v. 267, n. 3, p. 727?748, 4 abr. 1997. JUNQUEIRA, A. C. V. et al. Manual de Capacita??o na Detec??o de Trypanosoma cruzi para Microscopistas de Mal?ria e Laboratoristas da Rede P?blica (J. R. Coura, Ed.)Rio de Janeiro, 2011. KADISH, K. M.; SMITH, K. M.; GUILARD, R. The porphyrin handbook: Phthalocyanines: Spectroscopic and electrochemical characterization. The Porphyrin Handbook: Phthalocyanines: Spectroscopic and Electrochemical Characterization, v. 16, p. 1?288, 2 dez. 2012. KAWASAKI, Y.; FREIRE, E. Finding a better path to drug selectivityDrug Discovery TodayDrug Discov Today, , nov. 2011. Dispon?vel em: <https://pubmed.ncbi.nlm.nih.gov/21839183/>. Acesso em: 1 set. 2020 KHAMIS, M. A.; GOMAA, W.; AHMED, W. F. Machine learning in computational dockingArtificial Intelligence in MedicineElsevier, , 1 mar. 2015. Dispon?vel em: <https://linkinghub.elsevier.com/retrieve/pii/S0933365715000032>. Acesso em: 4 abr. 2021 KHAN, I. et al. Synthesis, antioxidant activities and urease inhibition of some new 1,2,4-triazole and 1,3,4-thiadiazole derivatives. European journal of medicinal chemistry, v. 45, n. 11, p. 5200?5207, nov. 2010. KIRTON, S. B. et al. Prediction of binding modes for ligands in the cytochromes P450 and other heme-containing proteins. Proteins: Structure, Function, and Bioinformatics, v. 58, n. 4, p. 836?844, 1 mar. 2005. KITCHEN, D. B. et al. Docking and scoring in virtual screening for drug discovery: methods and applications. Nature Reviews Drug Discovery, v. 3, n. 11, p. 935?949, nov. 2004. KORB, O.; ST?TZLE, T.; EXNER, T. E. Empirical scoring functions for advanced Protein-Ligand docking with PLANTS. Journal of Chemical Information and Modeling, v. 49, n. 1, p. 84?96, jan. 2009. KRAUTH-SIEGEL, R. L.; COMINI, M. A. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolismBiochimica et Biophysica Acta - General Subjects, nov. 2008. . Acesso em: 17 maio. 2021 KUPWADE, R. V. et al. Catalyst-free oxidation of sulfides to sulfoxides and diethylamine catalyzed oxidation of sulfides to sulfones using Oxone as an oxidant. Research on Chemical Intermediates 2017 43:12, v. 43, n. 12, p. 6875?6888, 7 jul. 2017. LARANJA, F. S. et al. Chagas? Disease A Clinical, Epidemiologic, and Pathologic Study, 2009. Dispon?vel em: <http://ahajournals.org>. Acesso em: 9 jun. 2020 LAZARDI, K.; URBINA, J. A.; DE SOUZA, W. Ultrastructural alterations induced by two ergosterol biosynthesis inhibitors, ketoconazole and terbinafine, on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi. Antimicrobial Agents and Chemotherapy, v. 34, n. 11, p. 2097?2105, 1990. LEONARD, N. J.; JOHNSON, C. R. Periodate Oxidation of Sulfides to Sulfoxides. Scope of the Reaction. Journal of Organic Chemistry, v. 27, n. 1, p. 282?284, 1 jan. 2002. LEPESHEVA, G. I. et al. Crystal structures of Trypanosoma brucei sterol 14?- demethylase and implications for selective treatment of human infections. Journal of Biological Chemistry, v. 285, n. 3, p. 1773?1780, 15 jan. 2010. LEPESHEVA, G. I. et al. VFV as a new effective CYP51 structure-derived drug candidate for chagas disease and visceral leishmaniasis. Journal of Infectious Diseases, v. 212, n. 9, p. 1439?1448, 1 nov. 2015. LEPESHEVA, G. I.; FRIGGERI, L.; WATERMAN, M. R. CYP51 as drug targets for fungi and protozoan parasites: past, present and future. Parasitology, v. 145, n. 14, p. 1820?1836, 1 dez. 2018. LEPESHEVA, G. I.; VILLALTA, F.; WATERMAN, M. R. Targeting Trypanosoma cruzi Sterol 14?-Demethylase (CYP51). In: Advances in Parasitology. [s.l.] Academic Press, 2011. v. 75p. 65?87. LEVINE, N. D. ET AL. A newly revised classification of the Protozoa. J. Protozool., v. 27, p. 37?58, 1980. LI, J.; FU, A.; ZHANG, L. An Overview of Scoring Functions Used for Protein? Ligand Interactions in Molecular DockingInterdisciplinary Sciences: Computational Life SciencesSpringer Berlin Heidelberg, , 1 jun. 2019. Dispon?vel em: <https://doi.org/10.1007/s12539-019-00327-w>. Acesso em: 22 abr. 2021 LI, L. et al. On the dielectric ?constant? of proteins: Smooth dielectric function for macromolecular modeling and its implementation in DelPhi. Journal of Chemical Theory and Computation, v. 9, n. 4, p. 2126?2136, 9 abr. 2013. LINDEN, R. Algoritmos Gen?ticos: Uma importante ferramenta da intelig?ncia computacional. Rio de Janeiro: Editora Brasport, 2006. LUQUETTI, A. O. et al. Congenital transmission of Trypanosoma cruzi in central Brazil. A study of 1,211 individuals born to infected mothers. Mem?rias do Instituto Oswaldo Cruz, v. 110, n. 3, p. 369?376, 14 mar. 2015. MACRAE, C. F. et al. Mercury CSD 2.0 ? new features for the visualization and investigation of crystal structures. Journal of Applied Crystallography, v. 41, n. 2, p. 466? 470, 1 abr. 2008. MANJULA, P. S. et al. The crystal structures of three 3-methyl-1H-1,2,4-triazole-5- thiones, including a second polymorph of 4-[(E)-(5-bromo-2-hydroxybenzylidene)amino]- 3-methyl-1H-1,2,4-triazole-5(4H)-thione and a redetermination of 4-amino-3-methyl-1H- 1,2,4-triazole-5(4H)-thione. Acta Crystallographica Section E: Crystallographic Communications, v. 71, p. 1003?1009, 2015. MARCH, J. Advanced Organic Chemistry-Reactions: Mecanism and Structure. 3a ed. ed. [s.l.] John Willley& Sons, 1985. MARTIN, M. B. et al. Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: A potential route to chemotherapy. Journal of Medicinal Chemistry, v. 44, n. 6, p. 909?916, 15 mar. 2001. MAVROVA, A. T. et al. Synthesis, cytotoxicity and effects of some 1,2,4-triazole and 1,3,4-thiadiazole derivatives on immunocompetent cells. European journal of medicinal chemistry, v. 44, n. 1, p. 63?69, jan. 2009. MAYA, J. D. et al. Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, v. 146, n. 4, p. 601?620, abr. 2007. MOOIJ, W. T. M.; VERDONK, M. L. General and targeted statistical potentials for protein-ligand interactions. Proteins: Structure, Function and Genetics, v. 61, n. 2, p. 272?287, 1 nov. 2005. MORGON, N. H.; COUTINHO, K. M?todos de qu?mica te?rica e modelagem molecular. 1. ed. S?o Paulo: Editora e Livraria da F?sica, 2007. MORILLO, C. A. et al. Benznidazole and Posaconazole in Eliminating Parasites in Asymptomatic T. Cruzi Carriers: The STOP-CHAGAS Trial. Journal of the American College of Cardiology, v. 69, n. 8, p. 939?947, 28 fev. 2017. MORRIS, G. M. et al. Automated docking using a Lamarckian Genetic Algorithm and an empirical binding free energy function. J. Comp. Chem, v. 19, p. 1639?1662, 1998. MURCIA, L. et al. Risk Factors and Primary Prevention of Congenital Chagas Disease in a Nonendemic Country. Clinical Infectious Diseases, v. 56, n. 4, p. 496?502, 15 fev. 2013. NAVEENA, C. S.; BOJA, P.; KUMARI, N. S. Synthesis, characterization and antimicrobial activity of some disubstituted 1,3,4-oxadiazoles carrying 2- (aryloxymethyl)phenyl moiety. European journal of medicinal chemistry, v. 45, n. 11, p. 4708?19, nov. 2010. N?BREGA, A. A. et al. Oral transmission of chagas disease by consumption of A?a? palm fruit, Brazil. Emerging Infectious Diseases, v. 15, n. 4, p. 653?655, abr. 2009. NOTREDAME, C.; HIGGINS, D. G.; HERINGA, J. T-coffee: A novel method for fast and accurate multiple sequence alignment. Journal of Molecular Biology, v. 302, n. 1, p. 205?217, 8 set. 2000. N??EZ-VERGARA, L. J. et al. Nitro radical anion formation from nifurtimox. Part 1: Biological evidences in Trypanosoma cruzi. Bioelectrochemistry and Bioenergetics, v. 43, n. 1, p. 151?155, 1 jun. 1997. OLIVEIRA, F. G. et al. Molecular docking study and development of an empirical binding free energy model for phosphodiesterase 4 inhibitors. Bioorganic & medicinal chemistry, v. 14, n. 17, p. 6001?11, 1 set. 2006. OPERA, T. I. Chemoinformatics in drug discovery. [s.l.] Weinheim: Wiley-VCH, 2005. OSORIO-M?NDEZ, J. F.; CEVALLOS, A. M. Discovery and genetic validation of chemotherapeutic targets for Chagas? diseaseFrontiers in Cellular and Infection MicrobiologyFrontiers Media S.A., , 7 jan. 2019. Dispon?vel em: <https://www.rcsb.>. Acesso em: 7 set. 2020 PAHO/WHO - Chagas Disease. Dispon?vel em: <https://www.paho.org/hq/index.php?option=com_content&view=category&layout=blog &id=3591&Itemid=3921&lang=en>. Acesso em: 1 abr. 2020. PAN AMERICAN HEALTH ORGANIZATION. Guidelines for the diagnosis and treatment of Chagas diseaseWashington, D.C, 2019. Dispon?vel em: <https://iris.paho.org/handle/10665.2/49653> PATTERSON, S. et al. Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: Discovery, synthesis, and characterization of their binding mode by protein crystallography. Journal of Medicinal Chemistry, v. 54, n. 19, p. 6514?6530, 13 out. 2011. PEREIRA, I. R. et al. A human type 5 adenovirus-based Trypanosoma cruzi therapeutic vaccine re-programs immune response and reverses chronic cardiomyopathy. PLoS pathogens, v. 11, n. 1, p. 1?26, 2015. P?REZ-AYALA, A. et al. Gastro-intestinal Chagas disease in migrants to Spain: Prevalence and methods for early diagnosis. Annals of Tropical Medicine and Parasitology, v. 105, n. 1, p. 25?29, jan. 2011. P?REZ-MOLINA, J. A.; MOLINA, I. Chagas disease. The Lancet, v. 391, n. 10115, p. 82?94, 2018. PETRAGLIA KROPF, S.; MASSARANI, L. Carlos Chagas, A ci?ncia para combater doen?as tropicais. p. 16, 2009. PINTO, A. Y. D. N. et al. Fase aguda da doen?a de Chagas na Amaz?nia brasileira. Estudo de 233 casos do Par?, Amap? e Maranh?o observados entre 1988 e 2005. Revista da Sociedade Brasileira de Medicina Tropical, v. 41, n. 6, p. 602?614, nov. 2008. PINTO DIAS, J. C. The indeterminate form of human chronic Chagas? disease. A clinical epidemiological reviewRevista da Sociedade Brasileira de Medicina TropicalSBMT, , 1989. . Acesso em: 9 jun. 2020 PODUST, L. M. et al. Estriol Bound and Ligand-free Structures of Sterol 14?- Demethylase. Structure, v. 12, n. 11, p. 1937?1945, nov. 2004. PODUST, L. M.; POULOS, T. L.; WATERMAN, M. R. Crystal structure of cytochrome P450 14?-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. v. 98, n. 6, 13 mar. 2001a. PODUST, L. M.; POULOS, T. L.; WATERMAN, M. R. Crystal structure of cytochrome P450 14alpha -sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proceedings of the National Academy of Sciences of the United States of America, v. 98, n. 6, p. 3068?73, 13 mar. 2001b. POLLACK, L. Historical Series: National Lecture. [s.l: s.n.]. Dispon?vel em: <https://www.ks.uiuc.edu/events/NationalLecture2015/reflection/>. Acesso em: 28 nov. 2021. POOLE, L. B. The basics of thiols and cysteines in redox biology and chemistryFree Radical Biology and MedicineElsevier Inc., , 2015. Dispon?vel em: <https://pubmed.ncbi.nlm.nih.gov/25433365/>. Acesso em: 12 set. 2020 PRATA, A. et al. Tratamento da Doen?a de Chagas pelo Nifurtimox (Bayer 2502). Revista da Sociedade Brasileira de Medicina Tropical, v. 9, n. 6, p. 297?307, dez. 1975. PREVIATO, L. Macromol?culas: Carboidratos de superf?cie do Trypanosoma cruzi. Dispon?vel em: <http://chagas.fiocruz.br/bioquimica/>. Acesso em: 10 set. 2020. PRIETO-MART?NEZ, F. D. et al. Computational Drug Design Methods?Current and Future Perspectives. In: In Silico Drug Design. [s.l.] Elsevier, 2019. p. 19?44. RASSI, A.; RASSI, A.; MARIN-NETO, J. A. Chagas diseaseThe LancetElsevier, , 17 abr. 2010. . Acesso em: 7 jun. 2020 RIBEIRO, T. S. et al. Toxic effects of natural piperine and its derivatives on epimastigotes and amastigotes of Trypanosoma cruzi. Bioorganic & Medicinal Chemistry Letters, v. 14, n. 13, p. 3555?3558, 5 jul. 2004. RILEY, J. et al. Development of a Fluorescence-based Trypanosoma cruzi CYP51 Inhibition Assay for Effective Compound Triaging in Drug Discovery Programmes for Chagas Disease. PLoS Neglected Tropical Diseases, v. 9, n. 9, p. 1?12, 2015. ROCHA JR., J. G. Desenvolvimento de um modelo emp?rico de prediss?o de atividade de inibidores da esterol 14alfa-desmetilase (CYP51) utilizando o m?todo semi-emp?rico PM6. UFRRJ: [s.n.]. ROCHA, S. F. L. DA S. Desenvolvimento de um Modelo Emp?rico de Predi??o da Atividade de Inibidores da Urease utilizando o M?todo Semi-Emp?rico PM6. [s.l: s.n.]. ROCHA, S. F. L. DA S. Desenvolvimento de um modelo emp?rico de predi??o da seletividade e da atividade de inibidores da Shp2 utilizando o m?todo semi-emp?rico PM7. Serop?dica: Universidade Federal Rural do Rio de Janeiro, 29 jan. 2019. SALD?VAR-GONZ?LEZ, F.; PRIETO-MART?NEZ, F. D.; MEDINA-FRANCO, J. L. Descubrimiento y desarrollo de f?rmacos: un enfoque computacional. Educacion Quimica, v. 28, n. 1, p. 51?58, 1 jan. 2017. SANT?ANNA; C. M. R. M?todos de modelagem molecular para estudo e planejamento de compostos bioativos: Uma introdu??o. Rev. Virtual Qu?m, v. 1, p. 49?57, 2009. SANTANNA, C. M. R. M?todos de modelagem molecular para estudo e planejamento de compostos bioativos : Uma introdu??o Resumo M?todos de modelagem molecular para estudo e planejamento de compostos bioativos : Uma introdu??o. Rev. Virtual Quim., v. 1, n. 1, p. 49?57, 2009. SCHMUNIS, G. A. Epidemiology of Chagas disease in non-endemic countries: The role of international migration. Memorias do Instituto Oswaldo Cruz. Anais...Funda??o Oswaldo Cruz, out. 2007. . Acesso em: 5 maio. 2020 SCOTTI, L. et al. Modelagem molecular aplicada ao desenvolvimento de mol?culas com atividade antioxidante visando ao uso cosm?tico. Revista Brasileira de Ci?ncias Farmac?uticas, v. 43, n. 2, p. 153?166, 2007. SHELDRICK, G. M. A short history of SHELXActa Crystallographica Section A: Foundations of CrystallographyInternational Union of Crystallography, , 1 jan. 2008. Acesso em: 31 mar. 2020 SHYADEHI, A. Z. et al. The mechanism of the acyl-carbon bond cleavage reaction catalyzed by recombinant sterol 14 alpha-demethylase of Candida albicans (other names are: lanosterol 14 alpha-demethylase, P-45014DM, and CYP51). The Journal of biological chemistry, v. 271, n. 21, p. 12445?12450, 1996. SIES, H.; BERNDT, C.; JONES, D. P. Oxidative Stress. Annual Review of Biochemistry, v. 86, n. 1, p. 715?748, 20 jun. 2017. SOSA, E. J. et al. Target-Pathogen: A structural bioinformatic approach to prioritize drug targets in pathogens. Nucleic Acids Research, v. 46, n. D1, p. D413?D418, 1 jan. 2018. SPINKS, D. et al. Design, synthesis and biological evaluation of Trypanosoma brucei Trypanothione Synthetase inhibitors. ChemMedChem, v. 7, n. 1, p. 95?106, 2 jan. 2012. STEINDEL, M. et al. Characterization of Trypanosoma cruzi isolated from humans, vectors, and animal reservoirs following an outbreak of acute human Chagas disease in Santa Catarina State, Brazil. Diagnostic
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universidade Federal Rural do Rio de Janeiro
dc.publisher.program.fl_str_mv Programa de P?s-Gradua??o em Qu?mica
dc.publisher.initials.fl_str_mv UFRRJ
dc.publisher.country.fl_str_mv Brasil
dc.publisher.department.fl_str_mv Instituto de Qu?mica
publisher.none.fl_str_mv Universidade Federal Rural do Rio de Janeiro
dc.source.none.fl_str_mv reponame:Biblioteca Digital de Teses e Dissertações da UFRRJ
instname:Universidade Federal Rural do Rio de Janeiro (UFRRJ)
instacron:UFRRJ
instname_str Universidade Federal Rural do Rio de Janeiro (UFRRJ)
instacron_str UFRRJ
institution UFRRJ
reponame_str Biblioteca Digital de Teses e Dissertações da UFRRJ
collection Biblioteca Digital de Teses e Dissertações da UFRRJ
bitstream.url.fl_str_mv http://localhost:8080/tede/bitstream/jspui/6553/4/2021+-+Larissa+Henriques+Evangelista+Castro.pdf.jpg
http://localhost:8080/tede/bitstream/jspui/6553/3/2021+-+Larissa+Henriques+Evangelista+Castro.pdf.txt
http://localhost:8080/tede/bitstream/jspui/6553/2/2021+-+Larissa+Henriques+Evangelista+Castro.pdf
http://localhost:8080/tede/bitstream/jspui/6553/1/license.txt
bitstream.checksum.fl_str_mv f29c2b45d33767a673000ca1f6da4c3b
4f9150ac64d28261cdaec5edfbee6cb3
0f6d9dd3eab2a65b6e1d58680ba9fbba
7b5ba3d2445355f386edab96125d42b7
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
repository.name.fl_str_mv Biblioteca Digital de Teses e Dissertações da UFRRJ - Universidade Federal Rural do Rio de Janeiro (UFRRJ)
repository.mail.fl_str_mv bibliot@ufrrj.br||bibliot@ufrrj.br
_version_ 1800313570347450368

Registros relacionados