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

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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.

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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

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Acknowledgments

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 (http://www.carriocas.org/) and funded by the French office “Direction Générale des Entreprises”.

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Authors and Affiliations

  1. MEDIT SA, 2 rue du Belvedere, 91120, Palaiseau, France

    Ksenia Oguievetskaia, Laetitia Martin-Chanas, Artem Vorotyntsev, Olivia Doppelt-Azeroual, Xavier Brotel, Stewart A. Adcock, Francois Delfaud & Fabrice Moriaud

  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 7, 6 rue Alexandre Cabanel, 75739, Paris Cedex 15, France

    Olivia Doppelt-Azeroual & Alexandre G. de Brevern

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  1. Ksenia Oguievetskaia
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  2. Laetitia Martin-Chanas
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  3. Artem Vorotyntsev
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  4. Olivia Doppelt-Azeroual
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  5. Xavier Brotel
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Correspondence to Ksenia Oguievetskaia.

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Ksenia Oguievetskaia and Laetitia Martin-Chanas contributed equally to this work.

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Oguievetskaia, K., Martin-Chanas, L., Vorotyntsev, A. et al. Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site. J Comput Aided Mol Des 23, 571–582 (2009). https://doi.org/10.1007/s10822-009-9286-z

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