Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site |
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Authors: | Ksenia Oguievetskaia Laetitia Martin-Chanas Artem Vorotyntsev Olivia Doppelt-Azeroual Xavier Brotel Stewart A Adcock Alexandre G de Brevern Francois Delfaud Fabrice Moriaud |
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Institution: | (1) MEDIT SA, 2 rue du Belvedere, 91120 Palaiseau, France;(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 |
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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.
Ksenia Oguievetskaia and Laetitia Martin-Chanas contributed equally to this work. |
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Keywords: | Fragment-based Drug design PDB Anti-mitotic Kinesin Allosteric pocket |
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