Study and Development of Theorical Modelo f Inhibition of the Enzyme Trypanothione Reductase of Leishmania spp. by a Class of N,N-diphenilbenzamidines. / Estudo e Desenvolvimento do Modelo Teórico de Inibição da Enzima Tripanotiona Redutase de Leishmania spp. por uma Classe de N,N-difenilbenzamidinas.

AUTOR(ES)
DATA DE PUBLICAÇÃO

2007

RESUMO

The present work aims to study and develop a theoretical model for the inhibition of trypanothione reductase from Leishmania spp by seven NN-diphenilbenzamidines, monosubstituted with the following groups: H, NO2, CH3, OCH3, CN, Br e Cl. Compounds were synthesized through a specific route and lately evaluated for a biological activity for some species of microorganisms, particularly trypanosomatids, showing interesting results. The methoxy-derived compound seemed to be very promising, due to its high activity against parasite plus its low citotoxicity for the host. Studies of enzymatic inhibition, performed in the Laboratório de Bioquímica de Tripanosomatídeos da Fundação Oswaldo Cruz (RJ) showed that this class of amidines has inhibitory activity for trypanothionereductase, essential to the parasite defense against cells of host immune system. Records in literature indicate this enzyme to be a strategical molecular target for the development of drugs against trypanosomatids. From experimental data of biological activity and structural models obtained from x-ray crystallography and molecular modeling, two hypothesis were set in order to elucidate the mechanism of enzyme inhibition by these compounds. The first one involved the possibility of a nucleophilic attack to the amidinic carbon by a sulfide group of Cis 52 presented in the enzyme active site. Nevertheless, stericals and thermodynamical disabilities showed that this is an improbable hypothesis. Considering that, in biological systems, aromatic compounds are usually submitted to epoxidation by enzymes such as, for example, cytochrome P450 epoxidase, we studied the possibility of an epoxided derivative of the original molecule exposed to parasite be the one involved in the formation of a covalently bounded complex to the enzyme. Data obtained from molecular modeling using semi-empirical method PM3 showed results that support this hypothesis indicating which amino acids are involved in the formation of enzyme-inhibitor complex for the developed models, additionally it was detected that the formation of covalent bound showed a favorable enthalpy of nearly -20 kcal.mol-1 for the studied epoxided amidines.

ASSUNTO(S)

amidines leishmania quimica organica modelagem molecular molecular modeling. tripanotiona redutase trypanohione reductase leishmania amidinas

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