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 potential drug target
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-11-14 → 2007-11-13
- EU contribution
- €157,652
- Participants
- 1
- Scheme
- EIF
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Results in brief
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.
Data: CORDIS, © European Union
Project objective
The trans-sialidase of Trypanosoma Cruzi (TcTS) has been identified as a potential target to fight the Chagas disease, which affects 16-18 million people in Latin America and lacks an effective cure. No effective inhibitor is known for TcTS. Therefore, a de tailed understanding of its mode of action and the associated energetics is of interest and could help the design of such an inhibitor. We propose to perform this study by computational means in tight collaboration with the crystallographic group in the Institute Pasteur (P. Alzari) to further exploit their data.On the one hand, we will analyse the contribution of different residues and ligand moieties to the binding affinities. For that, it appears important to take ligand and enzyme relaxation, as well as explicit solvent molecules into account because the recently solved high- resolution crystal structures have revealed conformational switches along the reaction and flexibility of the active site. We will use a molecular dynamics-based free energy method recently developed in the Pasteur Institute group, which fulfils these requirements and has predicted mutation effects with similar accuracy as the experiment. Furthermore, we propose to analyse the binding properties of new molecules made up of moieties taken from known ligands in order to attempt to identify the combinations giving tighter binders.This novel computational approach will, if successful, become a very valuable tool in other projects. On the other hand, we will study the chemical steps leading to the formation of a glycosyl-enzyme covalent intermediate allowing the trans-sialidase function whilst preventing the hydrolysis (sialidase function). A quantum mechanics/molecular mechanics potential will be used to understand how the enzyme forms this covalent intermediate and which proprieties of the ligand are important for this reaction. The results of this study will be useful to explore the design of a covalent inhibitor.
Original text from CORDIS.
Participants
- INSTITUT PASTEUR · PARISCoordinatorFrance
Links
Data: CORDIS, © European Union