Estudos computacionais de potenciais inibidores da enzima nucleosídeo hidrolase de Brucella suis

Abstract

Brucellosis is a zoonosis caused by bacteria of the genus Brucella. Despite the availability of chemotherapy against this disease today, the risk of resistance against these drugs is always present. Considering further the risk that this bacteria represents a biological warfare agent, it is imperative the search for new therapeutic targets and the development of new drugs agaisnt brucellosis. The enzyme nucleoside hydrolase (NH) is largely found in nature but not in mammals being, for this reason, seen as an ideal target to selective chemotherapy against parasitic and bacterial diseases. In line with this, was proposed in this work the three-dimensional structure of the NH from B.suis (BsNH), built through homology modeling, as a molecular target to the design of new drugs against brucelose. Further molecular docking studies, aiming to analyze the binding mode of the natural substrates and 4 known inhibitors of Chritidia fasciculata NH (CfNH) in the active site of BsNH were also performed. Subsequently, we carried out Molecular Dynamics (MD) simulations in order to check the docking results and select the most promising inhibitors as lead compounds to the design of potential inhibitors to BsNH. Additional docking and MD studies of these inhibitors and natural substrates with the CfNH were also performed in order to validate the protocol used. Due to the large sequence similarity between template and target (45,1%), it was possible to build a model to BsNH with an excellent stereochemical quality. Docking results, besides corroborating with the MD simulations, suggested a good correlation with experimental results. We also observed that CfNH inhibitors could, as well, be excellent BsNH inhibitors.