Journal of Computer-Aided Molecular Design

, Volume 23, Issue 8, pp 571–582 | Cite as

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

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

References

  1. 1.
    Mitchison TJ, Salmon ED (2001) Nat Cell Biol 3:E17. doi:10.1038/35050656 CrossRefGoogle Scholar
  2. 2.
    Mitchison T, Kirschner M (1984) Nature 312:237. doi:10.1038/312237a0 CrossRefGoogle Scholar
  3. 3.
    Mitchison TJ (1989) J Cell Biol 109:637. doi:10.1083/jcb.109.2.637 CrossRefGoogle Scholar
  4. 4.
    Vale RD, Fletterick RJ (1997) Annu Rev Cell Dev Biol 13:745. doi:10.1146/annurev.cellbio.13.1.745 CrossRefGoogle Scholar
  5. 5.
    Amos LA, Cross RA (1997) Curr Opin Struct Biol 7:239. doi:10.1016/S0959-440X(97)80032-2 CrossRefGoogle Scholar
  6. 6.
    Wood KW, Cornwell WD, Jackson JR (2001) Curr Opin Pharmacol 1:370. doi:10.1016/S1471-4892(01)00064-9 CrossRefGoogle Scholar
  7. 7.
    Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ (1999) Science 286:971. doi:10.1126/science.286.5441.971 CrossRefGoogle Scholar
  8. 8.
    Kwok BH, Kapoor TM (2007) Curr Opin Cell Biol 19:36. doi:10.1016/j.ceb.2006.12.003 CrossRefGoogle Scholar
  9. 9.
    Turner J, Anderson R, Guo J, Beraud C, Fletterick R, Sakowicz R (2001) J Biol Chem 276:25496. doi:10.1074/jbc.M100395200 CrossRefGoogle Scholar
  10. 10.
    Maliga Z, Kapoor TM, Mitchison TJ (2002) Chem Biol 9:989. doi:10.1016/S1074-5521(02)00212-0 CrossRefGoogle Scholar
  11. 11.
    Yan Y, Sardana V, Xu B, Homnick C, Halczenko W, Buser CA, Schaber M, Hartman GD, Huber HE, Kuo LC (2004) J Mol Biol 335:547. doi:10.1016/j.jmb.2003.10.074 CrossRefGoogle Scholar
  12. 12.
    Cox CD, Breslin MJ, Mariano BJ, Coleman PJ, Buser CA, Walsh ES, Hamilton K, Huber HE, Kohl NE, Torrent M, Yan Y, Kuo LC, Hartman GD (2005) Bioorg Med Chem Lett 15:2041. doi:10.1016/j.bmcl.2005.02.055 CrossRefGoogle Scholar
  13. 13.
    Cox CD, Torrent M, Breslin MJ, Mariano BJ, Whitman DB, Coleman PJ, Buser CA, Walsh ES, Hamilton K, Schaber MD, Lobell RB, Tao W, South VJ, Kohl NE, Yan Y, Kuo LC, Prueksaritanont T, Slaughter DE, Li C, Mahan E, Lu B, Hartman GD (2006) Bioorg Med Chem Lett 16:3175. doi:10.1016/j.bmcl.2006.03.040 CrossRefGoogle Scholar
  14. 14.
    Fraley ME, Steen JT, Brnardic EJ, Arrington KL, Spencer KL, Hanney BA, Kim Y, Hartman GD, Stirdivant SM, Drakas BA, Rickert K, Walsh ES, Hamilton K, Buser CA, Hardwick J, Tao W, Beck SC, Mao X, Lobell RB, Sepp-Lorenzino L, Yan Y, Ikuta M, Munshi SK, Kuo LC, Kreatsoulas C (2006) Bioorg Med Chem Lett 16:6049. doi:10.1016/j.bmcl.2006.08.118 CrossRefGoogle Scholar
  15. 15.
    Tarby CM, Kaltenbach RF3, Huynh T, Pudzianowski A, Shen H, Ortega-Nanos M, Sheriff S, Newitt JA, McDonnell PA, Burford N, Fairchild CR, Vaccaro W, Chen Z, Borzilleri RM, Naglich J, Lombardo LJ, Gottardis M, Trainor GL, Roussell DL (2006) Bioorg Med Chem Lett 16:2095. doi:10.1016/j.bmcl.2006.01.056 CrossRefGoogle Scholar
  16. 16.
    Kim KS, Lu S, Cornelius LA, Lombardo LJ, Borzilleri RM, Schroeder GM, Sheng C, Rovnyak G, Crews D, Schmidt RJ, Williams DK, Bhide RS, Traeger SC, McDonnell PA, Mueller L, Sheriff S, Newitt JA, Pudzianowski AT, Yang Z, Wild R, Lee FY, Batorsky R, Ryder JS, Ortega-Nanos M, Shen H, Gottardis M, Roussell DL (2006) Bioorg Med Chem Lett 16:3937. doi:10.1016/j.bmcl.2006.05.037 CrossRefGoogle Scholar
  17. 17.
    Garcia-Saez I, DeBonis S, Lopez R, Trucco F, Rousseau B, Thuery P, Kozielski F (2007) J Biol Chem 282:9740. doi:10.1074/jbc.M608883200 CrossRefGoogle Scholar
  18. 18.
    Jambon M, Imberty A, Deleage G, Geourjon C (2003) Proteins 52:137. doi:10.1002/prot.10339 CrossRefGoogle Scholar
  19. 19.
    Jambon M, Andrieu O, Combet C, Deleage G, Delfaud F, Geourjon C (2005) Bioinformatics 21:3929. doi:10.1093/bioinformatics/bti645 CrossRefGoogle Scholar
  20. 20.
    Doppelt O, Moriaud F, Bornot A, de Brevern AG (2007) Bioinformation 1:357Google Scholar
  21. 21.
    Moriaud F, Doppelt-Azeroual O, Martin L et al. (2009) J Chem Inf ModelGoogle Scholar
  22. 22.
    Doppelt-Azeroual O, Moriaud F, Delfaud F (2009) Infect Disord Drug TargetsGoogle Scholar
  23. 23.
    The PubChem Project (2008) http://pubchem.ncbi.nlm.nih.gov. Accessed 9 June 2008
  24. 24.
    Jambon M (2003) A bioinformatic system for searching functional similarities in 3D structures of proteins. Université Claude Bernard Lyon 1, LyonGoogle Scholar
  25. 25.
    Chen X, Lin Y, Liu M, Gilson MK (2002) Bioinformatics 18:130. doi:10.1093/bioinformatics/18.1.130 CrossRefGoogle Scholar
  26. 26.
  27. 27.
    Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK (2007) Nucleic Acids Res 35:D198. doi:10.1093/nar/gkl999 CrossRefGoogle Scholar
  28. 28.
    Nicholls A (2008) J Comput Aided Mol Des 22:239–255CrossRefGoogle Scholar
  29. 29.
    Gehlhaar DK, Verkhivker GM, Rejto PA, Sherman CJ, Fogel DB, Fogel LJ, Freer ST (1995) Chem Biol 2:317. doi:10.1016/1074-5521(95)90050-0 CrossRefGoogle Scholar
  30. 30.
    Czerminski R (2005) Conference presentation, http://www.eyesopen.com/about/events/cup6/
  31. 31.
    Jenkins JL, Glick M, Davies JW (2004) J Med Chem 47:6144. doi:10.1021/jm049654z CrossRefGoogle Scholar
  32. 32.
    Bemis GW, Murcko MA (1996) J Med Chem 39:2887. doi:10.1021/jm9602928 CrossRefGoogle Scholar
  33. 33.
    The Open Babel Package (2008) http://openbabel.sourceforge.net/. Accessed 5 July 2008
  34. 34.
    Accelrys Software Inc.: 10188 Telesis Court, Suite 100 San Diego, CA 92121, USA San DiegoGoogle Scholar
  35. 35.
  36. 36.
    Brooks BR, Bruccoleri RE, Olafson BD et al. (1983) J Comp Chem 187Google Scholar
  37. 37.
    Gehlhaar DK, Bouzida D, Rejto PA (1992) American Chemical Society: Washington DC 292Google Scholar
  38. 38.
    Jain AN (1996) J Comput Aided Mol Des 10:427. doi:10.1007/BF00124474 CrossRefGoogle Scholar
  39. 39.
    Krammer A, Kirchhoff PD, Jiang X, Venkatachalam CM, Waldman M (2005) J Mol Graph Model 23:395. doi:10.1016/j.jmgm.2004.11.007 CrossRefGoogle Scholar
  40. 40.
    Muegge I (2006) J Med Chem 49:5895. doi:10.1021/jm050038s CrossRefGoogle Scholar
  41. 41.
    Muegge I, Martin YC (1999) J Med Chem 42:791. doi:10.1021/jm980536j CrossRefGoogle Scholar
  42. 42.

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

Personalised recommendations