Journal of Computer-Aided Molecular Design

, Volume 23, Issue 8, pp 571–582

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

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

DOI: 10.1007/s10822-009-9286-z

Cite this article as:
Oguievetskaia, K., Martin-Chanas, L., Vorotyntsev, A. et al. J Comput Aided Mol Des (2009) 23: 571. doi:10.1007/s10822-009-9286-z

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 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.

Keywords

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

Abbreviations

SCF

Surface Chemical Feature

PDB

Protein Data Bank

KSP

Kinesin Spindle Protein

HYD

Hydrophobic

L5/α2

loop 5/helix α2

Å

Angström

Du

MED-Portion dummy atom

ROC

Receiver Operating Characteristic

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Ksenia Oguievetskaia
    • 1
  • 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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