The large volume of protein-ligand structures now available enables innovative and efficient protocols in computational FBDD (Fragment-Based Drug Design) to be proposed based on experimental data. In this work, we build a database of MED-Portions, where a MED-Portion is a new structural object encoding protein-fragment binding sites. MED-Portions are derived from mining all available protein-ligand structures with any library of small molecules. Combined with the MED-SuMo software to superpose similar protein interaction surfaces, pools of matching MED-Portions can be retrieved from any binding surface query. The rapidity of this technology allows its application to a diverse set of 107 protein binding sites. The selectivity of the protocol is shown by a qualitative correlation between the average hydrophobicity of the pools of MED-Portions and those of the binding sites. To generate hitlike molecules, MED-Portions are combined in 3D with the MED-Hybridise toolkit. Our MED-Portion/MED-SuMo/MED-Hybridise protocol is applied to two targets that represent important protein superfamilies in drug design: a protein kinase and a G-Protein Coupled Receptor (GPCR). We retrieved actives molecules of PubChem bioassays for the two targets. The results show the potential for finding relevant leads from any protein 3D structure since the occurrence of interfamily MED-Portions is 25% for protein kinase and almost 100% for the GPCR.

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.