title: Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site.
abstract: 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 loop 5/helix alpha2 (L5/alpha2). Recently designed inhibitors additionally occupy a hydrophobic pocket of this site. The goal of the present study was to explore this hydrophobic pocket with our MED-SuMo fragment-based protocol, and thus discover novel chemical structures that might bind as inhibitors. The MED-SuMo software is able to compare and superimpose similar interaction surfaces upon the whole protein data bank (PDB). In a fragment-based protocol, MED-SuMo retrieves MED-Portions that encode protein-fragment binding sites and are derived from cross-mining protein-ligand structures with libraries of small molecules. Furthermore we have excluded intra-family MED-Portions derived from Eg5 ligands that occupy the hydrophobic pocket and predicted new potential ligands by hybridization that would fill simultaneously both pockets. Some of the latter having original scaffolds and substituents in the hydrophobic pocket are identified in libraries of synthetically accessible molecules by the MED-Search software.
authors.affiliation: MEDIT SA, 2 rue du Belvedere, 91120, Palaiseau, France. ksenia@medit.fr
authors.forename: Ksenia
authors.initials: K
authors.lastname: Oguievetskaia
authors.forename: Laetitia
authors.initials: L
authors.lastname: Martin-Chanas
authors.forename: Artem
authors.initials: A
authors.lastname: Vorotyntsev
authors.forename: Olivia
authors.initials: O
authors.lastname: Doppelt-Azeroual
authors.forename: Xavier
authors.initials: X
authors.lastname: Brotel
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Adcock
authors.forename: Alexandre G
authors.initials: AG
authors.lastname: de Brevern
authors.forename: Francois
authors.initials: F
authors.lastname: Delfaud
authors.forename: Fabrice
authors.initials: F
authors.lastname: Moriaud
mesh_terms: D000495:Allosteric Site; D017076:Computer-Aided Design; D055808:Drug Discovery; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000627:therapeutic use; D012984:Software; D008941:Spindle Apparatus / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C470243:KIF11 protein, human; D008024:Ligands; D054852:Small Molecule Libraries; D016547:Kinesins