Modelagem molecular aplicada ao estudo de reações de inibição enzimática com aplicação potencial no controle de Leishmania amazonensis. 2010. / Applied molecular modeling to the enzymatic inhibition reactions study with Leishmania amazonensis controls potential application. 2010.

AUTOR(ES)
FONTE

IBICT - Instituto Brasileiro de Informação em Ciência e Tecnologia

DATA DE PUBLICAÇÃO

11/06/2010

RESUMO

Parasitic protozoan diseases, transmitted by blood-feeding insects, constitute the worlds 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

ASSUNTO(S)

quimica organica leishmania amazonensis molecular modeling amidinas mesoionics leishmania amazonensis modelagem molecular mesoiônicos amidines

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