JCJC - Jeunes chercheuses & jeunes chercheurs

Fragment-Based Hit Hunting in modern Structural Biochemistry Research – Fragscreens

Submission summary

Our objectives are: - - 1. Increase your library of low-molecular-weight molecules (improve - diversity, currently 260 molecules) - 2. Extend the experimental screening of fragments by NMR and by X-ray - crystallography - 3. Optimizing maturation strategies of fragment hits into potent - high-molecular-weight ligands - 4. Applying to different protein targets to get different therapeutics - goals: cancer, HCV, HIV, TB. - - Long-term goals - - Our long-term goals are: (a) the integration of Cheminformatics and - Molecular Modelling activities (CAMM) in experimental studies performed - by X-ray crystallography and Nuclear Magnetic Resonance (NMR) in the - laboratory. (b) the development of experimental screenings of small - molecules. (c) the development of the anti-cancer, anti-HIV, anti-HCV and - anti-tuberculosis area of researches. - - Abstract - - We propose to upgrade a fragment library dedicated to experimental - screenings by biophysical methods. Our first assumption is that - information about fragments that bind to a target (even weakly) can be - used to logically direct the design of more elaborated and more potent - molecules. The second assumption is that compounds containing molecular - fragments found in successful drugs are more likely to possess good ADME-T - properties than random molecules. Low-molecular-weight, weak binding - fragments are then connected to form high-affinity, - higher-molecular-weight ligands. - The approach is well related to the concept developed within our in-house - structure-based de novo drug design program LEA3D. It uses 'drug and bio' - fragments to conceive novel molecules. Our expertise of molecular - fragments will be useful in the present library design. - The binding mode of these fragments in the protein can be elucidated by - X-ray crystallography or by nuclear magnetic resonance (NMR). These - techniques are very effective at identifying weak interactions - (mM-mM). Fragment hits that have no measurable activity in a - biological assay can be identified. - Solving protein structures related to cancer and infectious diseases is a - theme of research in the laboratory. It also fits one of the research - axis, anti-infectious therapy, supported by the competitive pole 'ORPHEME' - recently validated by the 'Ministère de la Recherche'. We propose to - extend this area of research by developing the study of other families of - potential anti-cancer (Cyclophilin and Pin1), anti-HCV (Cyclophilin), - anti-HIV (Cyclophilin) and anti-tuberculosis (RPFs and Cyclophilin) - targets. As a test case for our fragment-based strategy, we will study by - NMR and X-ray crystallography, these proteins with fragments to identify - 'seeds' of more potent ligands. Additional collaborations completing the - characterization of hits will give insights on how these proteins work and - will determine if they are suitable targets for drug development. However, - we do not exclude that some other proteins may become application cases - for our fragment-based screening during this research program (nuclear - receptors and other anti-infectious proteins). ...

Project coordination

Jean François GUICHOU (Organisme de recherche)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Help of the ANR 150,000 euros
Beginning and duration of the scientific project: - 36 Months

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