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François Delfaud (aged 41) founded MEDIT on 2003. He obtained an exclusive licence in 2003 on the SuMo software technology from IBCP in Lyon (France) and lead the development of SuMo and of new applications in drug design related to SuMo. He is author of three international papers related to SuMo, and responsible for its global commercial development.
From 1997-2002, he was Account Manager at Accelrys, a leading company distributing softwares in molecular modelling, cheminformatics and bioinformatics to major pharmaceutical companies. He was responsible for business in Europe for up to 12M$, Team animation and Marketing events. His PhD work was done at Synthelabo Recherche (now Sanofi-Aventis) from 1994 to 1996. He worked on “Molecular Modeling study of interactions between Thrombin and its inhibitors" and was supervised by Jean-Claude Muller, now VP Sanofi-Aventis. Just after this, he spent 1 year as a software developer in a service company.
He currently has responsibilities in the IT competitiveness cluster System@tic where he is Vice President Technology Transfer and SMEs creation & development. In addition he is leading R&D projects both in this IT cluster and in the Medicen competitiveness cluster focused on drug development.
François holds a degree in Quantum Chemistry and Informatics, Orsay University, and he has been trained in NMR Structural Biology. He lives in Palaiseau, close to Paris, and is married with 3 children. He has French nationality.
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A Computational protocol to Fragment-Based Drug Design at PDB scale
Moriaud F. (1), Adcock S.A. (1), Vorotyntsev A.M. (1), Martin L. (1), Doppelt O. (1,2), De Brevern A.G. (2), Delfaud F. (1)
(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
Fragment- based drug design has emerged in the last decade and has become an established paradigm at many pharmaceutical companies. This exciting field has been recently reviewed [1]. The authors describe the impact on human diseases with a list of 47 potent inhibitors (IC50 < 100 nM) derived from experimentally driven fragment-based screening, three of them have entered clinical trials. Obtaining structural information on the fragment complexed to the protein target is a key factor 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 [2,3], a target based drug design tool, offers a procedure to adequately characterize the protein binding site. This tool is based on the identification of local shape and 3D Surface Chemical Features similarities in the target binding site with other proteins (with their co-crystallized ligands). MED-SuMo uses the binding site of the target as a query to search either the whole Protein Data Bank (or any corporate protein structure databank) for all the binding sites that display a local match with the query. This valuable information can then be used to identify which residues of the binding site are potentially important for ligand binding affinity and selectivity. As the similar binding sites are overlaid, the co-crystallized ligands are aligned and are therefore a starting material for ligand hybridization. Among the hundreds of overlaid binding sites generated by MED-SuMo, we found the protein-ligand complexes overlaid by Pierce et al. [4] as their starting material for ligand hybridization in the BREED method. Interestingly, they found relevant combinations of fragments starting from only a few protein-ligand complexes structures and we believe that the output of MED-SuMo is a very promising input for automatic methods like BREED. Alternatively, the fragments can be combined “by hand” while browsing the results within the MED-SuMo graphical user interface.
In this work, we used MED-SuMo on a fragment database derived from the PDB: each pdb file is converted into one or more pdb files containing a single fragment as ligand. MED-SuMo is used to query and mine the Surface Chemical Functions surrounding the fragments, seeking similarities with the protein of interest. A library of fragments positioned in the active site and annotated with the counts of contacts and h-bonds is generated. This is the basis of a protocol which ranks and hybridizes fragments. Fragmentation and hybridization steps are coupled with substructure searches in a database of chemical compounds from suppliers to increase the likelihood of fragments and hybridized molecules as synthetically feasible molecules.
References
(1) Hajduk PJ, Greer J. “A decade of fragment-based drug design: strategic advances and lessons learned” Nat Rev Drug Discov. 2007 Mar;6(3):211-9
(2) 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)
(3) 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)
(4) Pierce AC, Bemis GW, “BREED: generating novel inhibitors through hybridization of known ligands. Application to CDK2, p38, and HIV protease” J. Med. Chem. (2004) May 20;47(11):2768-75
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