Eg5, a mitotic kinesin exclusively involved in the formation and function of the mitotic spindle has attracted interest as an anticancer drug target. Eg5 is co-crystallized with several inhibitors bound to its allosteric binding pocket. Each of these occupies a pocket formed by loop5/helix α2. Recently designed inhibitors additionally occupy a hydrophobic pocket of this site. The goal of the present study was to identify new fragments which fill this hydrophobic pocket and might be interesting chemical moieties to design new inhibitors.We've used the fragment based protocol of MEDSuMo which exploits the whole PDB on the basis that similar protein surfaces might bind the same fragment. The MED-SuMo software is able to compare and superimpose similar protein-ligand interaction surfaces at PDB scale. Protein-fragment complexes are encoded as MED-Portions by cross-mining 3D PDB ligand structures with fragment-like PubChem molecules. Inhibitors are designed by hybridising MED-Portions with MEDHybridise.Without using the known Eg5 PDB ligands that occupy the hydrophobic pocket, we've predicted new potential ligands that would fill simultaneously both pockets. Some of the latter are identified in libraries of synthetically accessible molecules by the MED-Search software.

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Article signalé par l'éditeur en open access plus : http://www.eurekaselect.com/node/634/letters-in-drug-design-discovery/issue/9/503/1/4249International audienceDocking of lobeline, a partial agonist of nicotinic acetylcholine receptors (nAChRs), was investigated at once into crystallographic structures of acetylcholine binding proteins (AChBP) and into 7 and 42 nAChRs homology models, and compared to behavior of full agonists, nicotine and epibatidine. The homology models were built using as templates the different pocket geometries established in crystallographic AChBP structures. Systematic cross-docking of each ligand into binding pockets of the two other ligands as well as its self-docking into its own pocket were performed in order to better understand the structural features determining the binding of these three ligands chosen for their molecular diversity. In AChBPs, epibatidine and nicotine display similar docking scores in their own pocket and in other ligands pockets: in particular, they also dock favorably into the lobeline pocket. In opposite, lobeline displays different features: it only binds favorably to its own pocket in AChBPs. Furthermore, the docking poses observed starting from lobeline stereoisomers support the importance of the intramolecular hydrogen bond between the alcohol function of the-phenyl-hydroxyethyl arm and the piperidinium proton for the lobeline binding to AChBP. For homology models, cross-dockings are still discriminating and the specificity of lobeline for its binding pocket is conserved