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UFRRJ Catarina De Nigris Del Cistia UFRRJ INSTITUTO DE CIÊNCIAS EXATAS PROGRAMA DE PÓS-GRADUAÇÃO EM QUÍMICA TESE MODELAGEM MOLECULAR APLICADA AO ESTUDO DE REAÇÕES DE INIBIÇÃO ENZIMÁTICA COM APLICAÇÃO POTENCIAL NO CONTROLE DE Leishmania amazonensis Catarina De Nigris Del Cistia 2010 UNIVERSIDADE FEDERAL RURAL DO RIO DE JANEIRO INSTITUTO DE CIÊNCIAS EXATAS PROGRAMA DE PÓS-GRADUAÇÃO EM QUÍMICA MODELAGEM MOLECULAR APLICADA AO ESTUDO DE REAÇÕES DE INIBIÇÃO ENZIMÁTICA COM APLICAÇÃO POTENCIAL NO CONTROLE DE Leishmania amazonensis CATARINA DE NIGRIS DEL CISTIA Sob a orientação do Professor Carlos Maurício Rabello de Sant’Anna e Co-orientação da Professora Aurea Echevarria Tese submetida como requisito parcial para obtenção do grau de Doutor em Ciências, no Programa de Pós- Graduação em Química, Área de Concentração em Química Orgânica Seropédica, RJ Junho de 2010 UFRRJ / Biblioteca Central / Divisão de Processamentos Técnicos 547.21 D331m Del Cistia, Catarina de Nigris, 1980-. T Modelagem molecular aplicada ao estudo de reações de inibição enzimática com aplicação potencial no controle de Leishmania amazonensis / Catarina de Nigris Del Cistia – 2010. 193 f.: il. Orientador: Carlos Maurício Rabello de Sant’Anna. Tese (doutorado) – Universidade Federal Rural do Rio de Janeiro, Programa de Pós- Graduação em Química. Bibliografia: f. 144-159. 1. Síntese orgânica – Teses. 2. Leishmania - Teses. 3. Leishmaniose - Teses. 4. Inibidores enzimáticos – Teses. I. Sant’Anna, Carlos Maurício Rabello de, 1965-. II. Universidade Federal Rural do Rio de Janeiro. Programa de Pós-Graduação em Química. III. Título. “Os loucos abrem os caminhos que mais tarde os sábios percorrem.” James Joyce AGRADECIMENTOS . Aos meus pais Ana Maria De Nigris e Roberto Diniz Del Cistia, e aos irmãos Roberto e Guilherme De Nigris Del Cistia, pelo amor, paciência, apoio e carinho durante toda esta jornada. Ao orientador Prof. Dr. Carlos Maurício Rabello de Sant’Anna, principalmente pela amizade, paciência e compreensão, e por todo trabalho, incentivo, confiança, presença e transmissão de conhecimentos. Serei eternamente grata por todos os esclarecimentos, conselhos e atos. Ao namorado Rodrigo Medeiros, por todo amor, amizade, companhia, compreensão, ajuda, carinho e paciência. Sua ajuda e amor são de valia inestimável. Ao Prof. Dr. Marco Antônio Soares de Souza (USS), por todo trabalho, incentivo, exemplo, confiança e amizade por todos esses anos. Sem seu trabalho de iniciação científica, provavelmente eu não estaria nesta empreitada. Ao Prof. Dr. Marcos André Vannier dos Santos (FIOCRUZ), por todo material e explicações gentilmente cedidos; à Profª. Dra. Clarissa Oliveira da Silva (UFRRJ), pela convivência, incentivo, apoio e paciência. A todos os professores do Programa de Pós-Graduação em Química (PPGQ - UFRRJ) pelas aulas e conhecimentos transmitidos. Aos colegas de turma de mestrado Eliete, Welisson, Rodney e Kênia, aos grandes amigos Anivaldo e José Geraldo em especial, e aos companheiros de laboratório Fábio Javaroni, Jorge Fábio, Daniel, Nailton e tantos outros, por toda ajuda, compreensão, carinho, amizade, conselhos, paciência e companhia, a todo momento. Aos colegas de trabalho Harleson, Giuliano, Davyson, Sebastião, José Luis, Leonardo e Alacyr (UBM), e Cristiane, Evelize, Milane, Marco André, Luiz, Rafael, Sonia, Flavio, Marcelo, Ana Paula e vários outros (UFRRJ) por todo apoio, conselhos, ajuda e companhia nesta difícil jornada. Às companheiras de alojamento Maristella, Luciana, Michelle, Margareth, Livya, Natália, Antonieta, Amanda, Roberta, Bruna e Cinthya pela hospitalidade, companhia, ajuda, amizade e paciência. Aos amigos de Volta Redonda Thaís, Alessandra, Christian, Anna Carolina, Leonardo, Geraldo, Fernanda e tantos outros pela companhia, carinho, apoio, ajuda e compreensão em todos (e tantos) momentos difíceis. Aos funcionários e técnicos do PQ, por todo trabalho e convivência. Aos órgãos de fomento CAPES, CNPq e FAPERJ, por todo o auxílio concedido. A todos os membros da banca examinadora, por gentilmente aceitar o convite. E finalmente a Deus, por TUDO. RESUMO CISTIA, Catarina De Nigris Del. Modelagem molecular aplicada ao estudo de reações de inibição enzimática com aplicação potencial no controle de Leishmania amazonensis. 2010. 197p. Tese (Doutorado em Química Orgânica). Instituto de Ciências Exatas, Departamento de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, 2010. As doenças provocadas por protozoários, transmitidas principalmente por insetos hematófagos, constituem o problema de saúde humana mais distribuído no mundo, e estima- se que três milhões de indivíduos sofram de uma doença parasitária (principalmente pelos tripanossomatídeos e apicomplexa), responsáveis por importantes doenças humanas. Os compostos aqui estudados constituem as amidinas e os mesoiônicos, ambos sintetizados por Echevarria e colaboradores, UFRRJ. Este trabalho possui, como proposta inicial, uma procura por relações e equações que possuam boa correlação entre os valores de “ln(IC50)” calculados e os valores de “ln(IC50)” determinados experimentalmente, para determinar se o composto será ou não capaz de inibir as enzimas NO sintase (NOS) e tripanotiona redutase (TR) (em relação a enzimas pertencentes à Leishmania amazonensis). Como não há estruturas disponíveis da enzima TR para este organismo, um modelo foi feito através da técnica de modelagem por homologia, com um sequenciamento feito por laboratórios da FIOCRUZ [CASTRO-PINTO et al., 2008]. Esta estrutura foi usada para chegarmos aos resultados voltados realmente à Leishmania. As correlações foram procuradas através de 2 métodos diferentes: através do método de atracamento molecular (ou “docking”) e do método semi- empírico (com hamiltoniano PM3 [STEWART, 1989a,b]). Através destes métodos, foi analisada a probabilidade destes compostos se complexarem ao sítio ativo (como um inibidor isostérico), ou aos sítios do FAD e NADPH (como um inibidor alostérico). Frente aos compostos de atividade já conhecida analisados para montar o esquema (as fenotiazinas), encontrou-se que estes compostos se complexam melhor ao sítio ativo, atuando como inibidores isostéricos; porém os mesoiônicos e amidinas se complexam melhor ao sítio do FAD, caracterizando uma inibição alostérica. Frente ao padrão de atracamento destas moléculas no respectivo sítio, alterações foram propostas em suas estruturas básicas para fazer com que fiquem ainda mais ativos. Com isto, foram encontradas equações que possuem alta correlação entre os valores de ln(IC50) experimentais e calculados, fazendo com que estas equações possam ser usadas para a síntese de estruturas mais ativas, com menos efeitos colaterais. Palavras chave: Leishmania amazonensis, modelagem molecular, mesoiônicos, amidinas ABSTRACT CISTIA, Catarina De Nigris Del. Applied molecular modeling to the enzymatic inhibition reactions study with Leishmania amazonensis control’s potential application. 2010. 197p. Tese (Doctor Scientiae in Organic Chemistry). Instituto de Ciências Exatas, Departamento de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, 2010. Parasitic protozoan diseases, transmitted by blood-feeding insects, constitute the world’s most widely spread human health problem. It is estimated that three million people suffer from a parasitic infection (mainly trypanosomatid and apicomplexan parasites), responsible for important human diseases. The compounds here studied constitute the amidines and the mesoionics, synthesized by Echevarria and collaborators, UFRRJ. This work constitute, as an initial proposal, a search for relationships and equations that has good correlation between the calculated and experimental “ln(IC50)” values, to determinate the NO synthase (NOS) and trypanothione reductase (TR) inhibition capacity of the compounds (Leishmania amazonensis enzymes). A model was made through the homology modeling method, with a sequence made by FIOCRUZ laboratories [CASTRO-PINTO et al., 2008], as there are no TR enzyme available structures for this organism. This structure was used to get results really focused on Leishmania. The correlations were searched through 2 different methods: docking and semi-empirical methods (with PM3 parametric model [STEWART, 1989a,b]). Through these methods, the compounds active site binding probability (as an isosteric inhibitor) and the FAD and NADPH site binding probability (as an allosteric inhibitor) was analyzed. With the known activity compounds (the phenothiazines) used to build the model, the results shown that these compounds are better docked at the active site, acting as an isosteric inhibitor. However, the mesoionics and amidines dock better at the FAD binding site, featuring an allosteric inhibition. Through these molecules docking pattern at this binding site, structural alterations were proposed to make them even more active. High correlation equations were found between calculated and experimental ln(IC50). These equations can now be used for more active compounds synthesis, with less side effects. Key words: Leishmania amazonensis, molecular modeling, mesoionics, amidines LISTA DE FIGURAS Figura 1.1: Demonstrações microscópicas dos parasitos Trypanosoma brucei (forma evolutiva tripomastigota) [A], Trypanosoma cruzi (forma evolutiva epimastigotas) [B] e Leishmania donovani [C] (forma evolutiva promastigota).........................................................1 Figura 2.1: Fotos de William Boog Leishman (1865-1926) [A] e Charles Donovan (1863- 1915) [B], cientistas que primeiro descreveram parasitos do gênero Leishmania......................4
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