Currently, 7 to 8 million people are affected by Chagas disease, a parasitosis caused by T. cruzi. Currently the treatment for this disease is inadequate, there are only two drugs available and both can cause serious adverse effects and aren't active in the chronic phase of the disease. The silent-information regulator 2 proteins, otherwise called sirtuins, are currently considered as emerging anti-parasitic targets. Nicotinamide, a pan-sirtuin inhibitor, is known to cause kinetoplast alterations and the arrested growth of T. cruzi. In this work, modeling threading was used to determine the three-dimensional features of the sirtuin2 from T. cruzi. The choice of template by Modelling threading (human sirtuin 2 [hSir2] PDB code: 3ZGV) was based on highest degree of identity (46%) and low probability of error (2x10-68). The alignment of the structures' FASTA sequences was performed using the 4.5.4 SEAVIEW software, and the 3D model were built using MODELLER v9.14 program. From the lowest energy models obtained with MODELLER, we performed an analysis of Ramachamdran plot as main validation. We conducted a docking co factor (NAD+) in the model. The Molecular Dynamics (MD) was applied to refine the generated model. In MD we employed molecular force fields (amber99+ILDN), box water cubic 0,5, along with the addition of Na and Cl ions, in a physiological pH environment. The MD was initially performed with 20 ns to analyze the model behavior, then it was extended to 100 ns. For refinement of the analysis, the RMSD (Root-mean-square deviation) was analyzed. Other analyzes were also made during MD, such as: the turning radius, the hydrophobic area and RMSF (Measure of the average atomic mobility) that calculate regions which have high or low fluctuation during a period simulation or MD. Thus, the model built is presenting robust characteristics and can be used to search new inhibitors against Sirtuin 2.

Construction and validation of the 3D-structure of T. cruzi sirtuin-2 by modeling threading

251st National Meeting (2016)

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