Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site
| Autor: | François Delfaud, Stewart A. Adcock, Fabrice Moriaud, Olivia Doppelt-Azeroual, Artem Vorotyntsev, Laetitia Martin-Chanas, Alexandre G. de Brevern, Xavier Brotel, Ksenia Oguievetskaia |
|---|---|
| Přispěvatelé: | Molecular Extended Distribution in Information Technology (MEDIT), MEDIT SA, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Carriocas collaborative proje ct (h ttp://ww w.carriocas.org/) and funded by the French office 'Direction Générale des Entreprises., de Brevern, Alexandre G. |
| Rok vydání: | 2009 |
| Předmět: |
[SDV.BIO]Life Sciences [q-bio]/Biotechnology
Magnetic Resonance Spectroscopy Protein Data Bank (RCSB PDB) mitotic kinesins Kinesins Ligands 01 natural sciences 030226 pharmacology & pharmacy lcsh:Chemistry 0302 clinical medicine Drug Discovery [INFO.INFO-BT]Computer Science [cs]/Biotechnology [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM] 0303 health sciences [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] lcsh:T58.5-58.64 lcsh:Information technology Chemistry anti-mitotic Small molecule Computer Graphics and Computer-Aided Design fragment-based drug design [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] Eg5 Computer Science Applications 030220 oncology & carcinogenesis FBDD Kinesin Computer-Aided Design Hydrophobic and Hydrophilic Interactions PubChem Allosteric Site Protein Binding Stereochemistry Allosteric regulation Spindle Apparatus Biology Library and Information Sciences Small Molecule Libraries 03 medical and health sciences Structure-Activity Relationship [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Binding site Physical and Theoretical Chemistry KSP 030304 developmental biology 010405 organic chemistry Ligand Combinatorial chemistry 0104 chemical sciences [SDV.BIO] Life Sciences [q-bio]/Biotechnology Spindle apparatus Protein Structure Tertiary [INFO.INFO-BT] Computer Science [cs]/Biotechnology lcsh:QD1-999 Poster Presentation Helix [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] Function (biology) Software |
| Zdroj: | Journal of Computer-Aided Molecular Design Journal of Computer-Aided Molecular Design, Springer Verlag, 2009, 23 (8), pp.571-82. ⟨10.1007/s10822-009-9286-z⟩ Journal of Cheminformatics Journal of Cheminformatics, Vol 2, Iss Suppl 1, p P29 (2010) |
| ISSN: | 1573-4951 0920-654X |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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