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Trans-Sialidase of Trypanosoma Cruzi: Analysis by molecular dynamics and QM/MM methods of the reaction and the ligand affinity of a potential drug target

Final Activity Report Summary - MASGRAU_TCTS_05 (Trans-sialidase of trypanosoma cruzi : Analysis by molecular dynamics and QM/MM Methods of the reaction and the ligand affinity of a ... drug target)

The trans-sialidase of Trypanosoma cruzi (TcTS) is an enzyme identified as a potential target to fight the Chagas disease, which affects 16-18 million people in Latin America and lacks an effective cure. Trypanosomes cannot synthesise sialic acid and they use this enzyme to scavenge it from the host. The inhibition of TcTS would be fatal for the parasite, but so far no good inhibitor is known for TcTS. Conversly, viral and Trypanosoma sialidases (i.e. Trypanosoma rangeli Sialidase, TrSA) are inhibited by a compound called DANA.

The aim of this project was an in depth analysis of the process of ligand binding by TcTS in order to help in the design of an inhibitor. This has been done by computational means. We have compared the binding affinities of different ligands, including DANA, for TcTS and TrSA. The weaker relative affinity of TcTS for DANA has been successfully analysed.Our results indicate that conformational flexibility may be preventing the identification of an inhibitor, as it appears to weaken inhibitor binding. Further analysis of this effect is being performed.

Finally, we have extended out study to the Trypanosoma cruzi proline racemase. This enzyme, which crystal structure was solved in the crystallographic laboratory of the Institut Pasteur, has been identified also as drug target against Chagas disease.