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Fabrice Moriaud joined MEDIT on 2004 as CSO where he is heading the R&D and drug design services. He manages the collaborations with academic groups and with partners in the French competitiveness clusters Medicen. He brought to MEDIT his experience of drug design in interaction with medicinal chemists from Sanofi-Synthelabo and his background in, chemistry, computational chemistry and biochemistry.
From 2002 to 2004, he was a Postdoctoral fellow at Sanofi-Synthelabo (Strasbourg, FR) where he worked as molecular modeler interacting with medicinal chemists. He developed a predictive code and integrated it within a graphical user interface. From 1999 to 2001, he was a postdoctoral fellow at Leiden University (Leiden, NL) where he trained in biochemistry and spectroscopy of proteins. Fabrice holds a Ph.D. in chemistry from the Grenoble Joseph Fourier University. He was hosted at the CEA Grenoble where he used magnetic resonance and quantum chemistry to unravel the magnetic properties of bioinorganic mimics of Iron-sulfur Proteins. He has trained in protein structure determination by nuclear magnetic resonance, quantitative structure-activity relationships and alloys crystallography.
He lives in Paris and has one child. He has French nationality.
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Exploration of the Chemical Diversity Generated by the Hybridisation of PDB Ligands
F. Moriaud, L. Martin, S.A. Adcock, A.M. Vorotyntsev, F. Delfaud (1) and O. Doppelt (1,2)
(1) MEDIT SA, 2, rue du belvédère, 91120, Palaiseau, France
(2) INSERM, U726, Equipe de Bioinformatique Genomique et Moleculaire (EBGM), Universite Paris 7,case 7113, 2, place Jussieu, 75251 Paris Cedex 05, France
The number and diversity of available protein/ligand complexes in the PDB are growing. Obtaining structural information on fragments complexed to a target protein is a key element and also a major limitation to the number and types of target that are amenable to fragment-based approaches. Therefore, computational methods are needed to mine efficiently all the available 3D structures of ligands complexed to proteins, both treated as a whole and as smaller fragments to increase the likelihood of fragment hopping from one target to another.
MED-SuMo[1,2] is used on a fragment database derived from the PDB protein-ligand complexes: each PDB file is converted into one or more PDB files containing the protein and a single fragment of the former ligand, with its original 3D coordinates. The fragments are stored in a MED-SuMo database as MED-Portions (500,000 entries). MED-Portions are fragments of PDB ligands annotated with dummy/bonding atoms and their 3D protein environment described by surface chemical features. A target protein surface/binding site is populated with fragments by searching with MED-SuMo for MED-Portions sharing a 3D graph of triangles of surface chemical features. Potential leads are discovered by hybridisation of MED-Portions with a de novo protocol using MED-Hybridise.
In this work, we use the MED-SuMo fragment based approach to explore the molecular diversity that can be generated by considering a diverse set of protein binding sites and by (1) populating their binding sites with fragments, (2) hybridising fragments into drug-like molecules. The protocol is able to generate valuable hybrids for a lead discovery approach. Hybrids are found to be diverse compared to the PDB: 99% of the hybrids have a scaffold which is not found in the PDB (results from a protein kinase and a GPCR application). The quality of the hybrids are assessed by computing their strained energy and the occurrence of their scaffold in Pubchem.
References
[1] Jambon M, Imberty A, Deléage G, Geourjon C “A new bioinformatic approach to detect common 3D sites in protein structures” PROTEINS: Structure, Function, and Genetics 52:137-145 (2003)
[2] Jambon M, Andrieu O, Combet C, Deléage G, Delfaud F, Geourjon C “The SuMo server : 3D search for protein functional sites” Bioinformatics Vol 21, n°20, 3929-3930 (2005)
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