Journal of Molecular Modeling

, Volume 15, Issue 2, pp 183–192 | Cite as

Elucidation of binding mode and three dimensional quantitative structure–activity relationship studies of a novel series of protein kinase B/Akt inhibitors

  • M. Muddassar
  • F. A. Pasha
  • M. M. Neaz
  • Y. Saleem
  • S. J. ChoEmail author
Original Paper


Protein kinase B (PKB; also known as Akt kinase) is located downstream in the PI-3 kinase pathway. Overexpression and constitutive activation of PKB/Akt leads to human prostate, breast and ovarian carcinomas. A series of 69 PKB/Akt inhibitors were examined to explore their binding modes using FlexX, and three-dimensional quantitative structure–activity relationship (3D-QSAR) studies based on comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed to provide structural insights into these compounds. CoMFA produced statistically significant results, with cross-validated q 2 and non-cross validated correlation r 2 coefficients of 0.53 and 0.95, respectively. For CoMSIA, steric, hydrophobic and hydrogen bond acceptor fields jointly yielded ‘leave one out’ q 2  = 0.51 and r 2  = 0.84. The predictive power of CoMFA and CoMSIA was determined using a test set of 13 molecules, which gave correlation coefficients, \(r_{{\text{predictive}}}^2 \) of 0.58 and 0.62, respectively. Molecular docking revealed that the binding modes of these molecules in the ATP binding sites of the Akt kinase domain were very similar to those of the co-crystallized ligand. The information obtained from 3D contour maps will allow the design of more potent and selective Akt kinase inhibitors.


3D QSAR Inhibitors Molecular docking Protein kinase B 



This work was supported by a Korea Science and Engineering Foundation(KOSEF) grant funded by the Korean government (MEST) through the Research Center for Resistant Cells (R13-2003-009). We are thankful to Hwan Won Jung and Jung Soo Oh for assistance in using the computational facilities.


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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • M. Muddassar
    • 1
    • 2
  • F. A. Pasha
    • 1
  • M. M. Neaz
    • 1
    • 2
  • Y. Saleem
    • 1
    • 2
  • S. J. Cho
    • 1
    • 3
    • 4
    Email author
  1. 1.Future Fusion Technology Division, Computational Science CenterKorea Institute of Science and TechnologySeoulSouth Korea
  2. 2.School of ScienceUniversity of Science and TechnologyDaejeonSouth Korea
  3. 3.College of MedicineChosun UniversityGwangjuSouth Korea
  4. 4.Research Center for Resistant CellsChosun UniversityGwangjuSouth Korea

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