Currently, 6 to 8 million people are affected by Chagas disease, a parasitose caused by Tripanossoma cruzi. Chaga’s disease is endemic in Latin America but has spread to other continents by migratory movements. Every year, there are 56,000 new cases and approximately 12,000 deaths from complications of the disease. Actually, there are only two drugs available to the treatment, Nifurtimox and Benzonidazole, but are effective only in the acute phase, present several side effects and parasite resistense1. Face of this panorama, it is imminent need to new drugs against T. cruzi. One of the most important enzymes for Trypanosoma cruzi infection is the Silent information regulator 2 (Sir-2), which is NAD+ dependent class III histone deacetylases. In this context we use modeling threading to perform the construction of the T. cruzi Sir-2 (tcSir2) and Molecular Dynamics method to refine the model to be used in the strategy of Structure-Based Drug Design (SBDD). 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 model construction was performed in two steps: alignment (1D) of the sequences in 4.5.4 SEAVIEW software; and building of the 3D model with MODELLER v9.14 program. The Ramachamdran plot of the lowest energy models was presenting 0.5% outliers (Figure 1), as main validation. We used Molecular Dynamic (MD) calculations to refine the model, that employed in Gromacs program using molecular force fields (amber99+ILDN), box water cubic 0,5, ions Cl and Na was added, the concentration used was physiological pH. The MD were performed for 100 ns, and the model was stable after 40ns. The figure below shows the model after MD was observed it was stable and also that the model has the same fold selected template (PDB code: 3ZGV) in finger example zinc residues were forecast in the same conformation is important to keep the fold.

Trypanosoma cruzi sirtuin-2 construction by modeling threading and molecular dynamics

253rd National Meeting (2017)

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