Skip to Main content Skip to Navigation
Journal articles

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.
Complete list of metadatas

Cited literature [16 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-00396557
Contributor : Alexandre G. de Brevern <>
Submitted on : Thursday, June 18, 2009 - 2:33:51 PM
Last modification on : Saturday, March 28, 2020 - 2:15:16 AM
Long-term archiving on: : Tuesday, June 15, 2010 - 5:39:12 PM

Files

KO_LCM_JCAMD.pdf
Files produced by the author(s)


Identifiers

Collections

Citation

Ksenia Oguievetskaia, Laetitia Martin-Chanas, Artem Vorotyntsev, Olivia Doppelt-Azeroual, Xavier Brotel, et al.. Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site.. Journal of Computer-Aided Molecular Design, Springer Verlag, 2009, 23 (8), pp.571-82. ⟨10.1007/s10822-009-9286-z⟩. ⟨inserm-00396557⟩

Share

Metrics

Record views

483

Files downloads

1925