Journal of Computer-Aided Molecular Design

, Volume 23, Issue 8, pp 571–582 | Cite as

Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site

  • Ksenia OguievetskaiaEmail author
  • Laetitia Martin-Chanas
  • Artem Vorotyntsev
  • Olivia Doppelt-Azeroual
  • Xavier Brotel
  • Stewart A. Adcock
  • Alexandre G. de Brevern
  • Francois Delfaud
  • Fabrice Moriaud


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 α2 (L5/α2). 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.


Fragment-based Drug design PDB Anti-mitotic Kinesin Allosteric pocket 



Surface Chemical Feature


Protein Data Bank


Kinesin Spindle Protein




loop 5/helix α2




MED-Portion dummy atom


Receiver Operating Characteristic



We thank Raphaël Guerois for providing us useful comments and suggestions for the initiation of this study (Commissariat à l’Energie Atomique (CEA), Institut de Biologie et Technologies de Saclay, and Centre National de la Recherche Scientifique (CNRS), Gif-sur-Yvette, F-91191, France). Olivia Doppelt-Azeroual was funded by the ANRT. This work was supported by the Carriocas collaborative project ( and funded by the French office “Direction Générale des Entreprises”.


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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Ksenia Oguievetskaia
    • 1
    Email author
  • Laetitia Martin-Chanas
    • 1
  • Artem Vorotyntsev
    • 1
  • Olivia Doppelt-Azeroual
    • 1
    • 2
  • Xavier Brotel
    • 1
  • Stewart A. Adcock
    • 1
  • Alexandre G. de Brevern
    • 2
  • Francois Delfaud
    • 1
  • Fabrice Moriaud
    • 1
  1. 1.MEDIT SAPalaiseauFrance
  2. 2.INSERM UMR-S 665, Equipe DSIMB, Dynamique des Structures et Interactions des Macromolécules Biologiques, Institut National de Transfusion Sanguine (INTS)Université Paris Diderot—Paris 7Paris Cedex 15France

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