Skip to main content
SpringerLink
Log in

Homology modeling, molecular dynamic simulation and docking studies of cyclin dependent kinase 1

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

In order to develop promising cyclin dependent kinase 1 inhibitors, homology modeling, docking and molecular dynamic simulation techniques were applied to get insight into the functional and structural properties of cyclin dependent kinase 1 (CDK1). Since there is no reported CDK1 crystal structural data, the three dimensional structure of CDK1 was constructed based on homology modeling. An extensive dynamic simulation was also performed on a Flavopiridol-CDK1 complex for probing the binding pattern of Flavopiridol in the active site of CDK1. The binding modes of other inhibitors to CDK1 were also proposed by molecular docking. The structural requirement for developing more potent CDK1 inhibitors was obtained by the above-mentioned molecular simulations and pharmacophore modeling.

Since there is no reported CDK1 crystal structural data, the three dimensional structure of CDK1 was constructed based on homology modeling herein. An extensive dynamic simulation was also performed on a Flavopiridol-CDK1 complex for probing the binding pattern of Flavopiridol in the active site of CDK1.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Lees E (1995) Curr Opin Cell Biol 7:773–780

    Article  CAS  Google Scholar 

  2. Morgan DO (1997) Annu Rev Cell Dev Bi 13:261–291

    Article  CAS  Google Scholar 

  3. Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massague J, Pavletich NP (1995) Nature 376:313–320

    Article  CAS  Google Scholar 

  4. Dunphy WG (1994) Trends Cell Biol 4:202–207

    Article  CAS  Google Scholar 

  5. Hoffman I, Karsenti E (1994) J Cell Sci 18:75–79

    Google Scholar 

  6. Hochegger H, Takeda S, Hunt T (2008) Nat Rev Mol Cell Bio 9:910–U926

    Article  CAS  Google Scholar 

  7. Knockaert M, Greengard P, Meijer L (2002) Trends Pharmacol Sci 23:417–425

    Article  CAS  Google Scholar 

  8. Villerbu N, Gaben AM, Redeuilh G, Mester J (2002) Int J Cancer 97:761–769

    Article  CAS  Google Scholar 

  9. Havlicek L, Hanus J, Vesely J, Leclerc S, Meijer L, Shaw G, Strnad M (1997) J Med Chem 40:408–412

    Article  CAS  Google Scholar 

  10. Moon MJ, Lee SK, Lee JW, Song WK, Kim SW, Kim JI, Cho C, Choi SJ, Kim YC (2006) Bioorg Med Chem 14:237–246

    Article  CAS  Google Scholar 

  11. Joshi KS, Rathos MJ, Joshi RD, Sivakumar M, Mascarenhas M, Kamble S, Lal B, Sharma S (2007) Mol Cancer Ther 6:918–925

    Article  CAS  Google Scholar 

  12. DePinto W, Chu XJ, Yin XF, Smith M, Packman K, Goelzer P, Lovey A, Chen YS, Qian H, Hamid R, Xiang Q, Tovar C, Blain R, Nevins T, Higgins B, Luistro L, Kolinsky K, Felix B, Hussain S, Heimbrook D (2006) Mol Cancer Ther 5:2644–2658

    Article  CAS  Google Scholar 

  13. Byth KF, Geh C, Forder CL, Oakes SE, Thomas AP (2006) Mol Cancer Ther 5:655–664

    Article  CAS  Google Scholar 

  14. Aoyagi Y, Masuko N, Ohkubo S, Kitade M, Nagai K, Okazaki S, Wierzba K, Terada T, Sugimoto Y, Yamada Y (2005) Cancer Sci 96:614–619

    Article  CAS  Google Scholar 

  15. Brana MF, Cacho M, Garcia ML, Mayoral EP, Lopez B, de Pascual-Teresa B, Ramos A, Acero N, Llinares F, Munoz-Mingarro D, Lozach O, Meijer L (2005) J Med Chem 48:6843–6854

    Article  CAS  Google Scholar 

  16. Sielecki TM, Boylan JF, Benfield PA, Trainor GL (2000) J Med Chem 43:1–18

    Article  CAS  Google Scholar 

  17. Dasmahapatra GP, Didolkar P, Alley MC, Ghosh S, Sausville EA, Roy KK (2004) Clin Cancer Res 10:5242–5252

    Article  CAS  Google Scholar 

  18. Grosios K (2001) Curr Opin Invest Drugs 2:287–297

    CAS  Google Scholar 

  19. Schmid WF, John RO, Muhlgassner G, Heffeter P, Jakupec MA, Galanski M, Berger W, Arion VB, Keppler BK (2007) J Med Chem 50:6343–6355

    Article  CAS  Google Scholar 

  20. Li YL, Fang H, Xu WF, Wang BH (2008) Chin Chem Lett 19:541–543

    Article  Google Scholar 

  21. Shi JY, Blundell TL, Mizuguchi K (2001) J Mol Biol 310:243–257

    Article  CAS  Google Scholar 

  22. Blundell TL, Elliott G, Gardner SP, Hubbard T, Islam S, Johnson M, Mantafounis D, Murray-Rust P, Overington J, Pitts JE, Sali A, Sibanda BL, Singh J, Sternberg MJE, Sutcliffe MJ, Thornton JM, Travers P (1989) Phil Trans R Soc Lond B 324:447–460

    Article  CAS  Google Scholar 

  23. Lüthy R, McLachlan AD, David E (1991) Proteins 10:229–239

    Article  Google Scholar 

  24. Lüthy R, Bowie JU, Eisenberg D (1992) Nature 356:83–85

    Article  Google Scholar 

  25. Berendsen HJC, van der Spoel D, van Drunen R (1995) Comput Phys Commun Package 91:43–56

    Article  CAS  Google Scholar 

  26. Lindahl E, Hess B, van der Spoel D (2001) J Mol Model 7:306–317

    CAS  Google Scholar 

  27. Van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC (2005) J Comput Chem 26:1701–1718

    Article  Google Scholar 

  28. Brusselbach S, Nettelbeck DM, Sedlacek HH, Muller R (1998) Int J Cancer 77:146–152

    Article  CAS  Google Scholar 

  29. Rarey M, Kramer B, Lengauer T, Klebe G (1996) J Mol Biol 261:470–489

    Article  CAS  Google Scholar 

  30. Rarey M, Kramer B, Lengauer T (1997) J Comput Aided Mol Des 11:369–384

    Article  CAS  Google Scholar 

  31. Darden T, York D, Pedersen L (1993) J Chem Phys 98:10089–10092

    Article  CAS  Google Scholar 

  32. McClue SJ, Blake D, Clarke R, Cowan A, Cummings L, Fischer PM, MacKenzie M, Melville J, Stewart K, Wang SD, Zhelev N, Zheleva D, Lane DP (2002) Int J Cancer 102:463–468

    Article  CAS  Google Scholar 

  33. Gherardi D, D’Agati V, Chu THT, Barnett A, Gianella-Borradori A, Gelman IH, Nelson PJ (2004) J Am Soc Nephrol 15:1212–1222

    Article  CAS  Google Scholar 

  34. Kim KS, Sack JS, Tokarski JS, Qian LG, Chao ST, Leith L, Kelly YF, Misra RN, Hunt JT, Kimball SD, Humphreys WG, Wautlet BS, Mulheron JG, Webster KR (2000) J Med Chem 43:4126–4134

    Article  CAS  Google Scholar 

  35. Clement OA, Mehl AT (2000) HipHop: pharmacophores based on multiple common-feature alignments. In: Güner OF (ed) Pharmacophore Perception. Development & Use In Drug Design. International University Line, La Jolla, pp 69–84

    Google Scholar 

  36. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) J Comput Chem 25:1605–1612

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Project of Science and Technology Research in Shandong Province (2008GG10002010) and Independent Innovation Foundation of Shandong University, IIFSDU (2009TS111). We also acknowledge Accelrys Inc. for providing the Discovery Studio 2.5 package.

Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Jinan, Shandong, 250012, China

    Lei Zhang, Huawei Zhu, Qiang Wang, Hao Fang, Wenfang Xu & Minyong Li

Authors
  1. Lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huawei Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hao Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenfang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Minyong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wenfang Xu or Minyong Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, L., Zhu, H., Wang, Q. et al. Homology modeling, molecular dynamic simulation and docking studies of cyclin dependent kinase 1. J Mol Model 17, 219–226 (2011). https://doi.org/10.1007/s00894-010-0710-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-010-0710-z

Keywords

Search

Navigation