Projet ANR-07-JCJC-0046 – Fragscreens : Fragment-Based Hit Hunting in modern Structural Biochemistry Research
Programme : Jeunes chercheuses & jeunes chercheurs (JCJC) 2007
Année de financement : 2007
Coordinateur du projet : CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE LANGUEDOC-ROUSSILLON (CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE LANGUEDOC-ROUSSILLON)
Partenaires : Centre national de la recherche scientifique
Montant : 150000.0 euros
Date de début : 2007
Durée : 36 mois
Résumé : 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).                                                                                                                                                                                                                                                                                                                                                                                                                                                      ...