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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- engineering and technology materials engineering crystals
- natural sciences physical sciences quantum physics
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP6-2004-MOBILITY-5
See other projects for this call
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
PARIS
France
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.