2D and 3D QSAR models for identifying diphenylpyridylethanamine based inhibitors against cholesteryl ester transfer protein

https://doi.org/10.1016/j.bmcl.2015.08.080Get rights and content

Abstract

Cholesteryl ester transfer protein (CETP) inhibitors hold promise as new agents against coronary heart disease. Molecular modeling techniques such as 2D-QSAR and 3D-QSAR analysis were applied to establish models to distinguish potent and weak CETP inhibitors. 2D and 3D QSAR models-based a series of diphenylpyridylethanamine (DPPE) derivatives (newly identified as CETP inhibitors) were then performed to elucidate structural and physicochemical requirements for higher CETP inhibitory activity. The linear and spline 2D-QSAR models were developed through multiple linear regression (MLR) and support vector machine (SVM) methods. The best 2D-QSAR model obtained by SVM gave a high predictive ability (R2train = 0.929, R2test = 0.826, Q2LOO = 0.780). Also, the 2D-QSAR models uncovered that SlogP_VSA0, E_sol and Vsurf_DW23 were important features in defining activity. In addition, the best 3D-QSAR model presented higher predictive ability (R2train = 0.958, R2test = 0.852, Q2LOO = 0.734) based on comparative molecular field analysis (CoMFA). Meanwhile, the derived contour maps from 3D-QSAR model revealed the significant structural features (steric and electronic effects) required for improving CETP inhibitory activity. Consequently, twelve newly designed DPPE derivatives were proposed to be robust and potent CETP inhibitors. Overall, these derived models may help to design novel DPPE derivatives with better CETP inhibitory activity.

Section snippets

Acknowledgements

The authors thank Professor Ji Z.L. for his technological help. This work is supported by Fujian Provincial Natural Science fund subject (2015J01340), National Natural Science Foundation program (81503497), the key discipline special program of Fujian University of Traditional Chinese Medicine (X2014012) and Fujian Provincial Traditional Chinese Medicine Science and Technology program (wzrk201303).

References and notes (27)

  • T.R. Joy

    Pharmacol. Ther.

    (2012)
  • D. Bloomfield et al.

    Am. Heart J.

    (2009)
  • M.M. Miller et al.

    Bioorg. Med. Chem. Lett.

    (2012)
  • S.M. Tan et al.

    Chemometr. Intell. Lab. Syst.

    (2010)
  • L.T. Qin et al.

    Chemosphere

    (2013)
  • M. Jalali-Heravi et al.

    Eur. J. Med. Chem.

    (2008)
  • Y. Zhao et al.

    J. Hazard. Mater.

    (2014)
  • M. Zhong et al.

    Bioorg. Med. Chem. Lett.

    (2013)
  • M. Goodarzi et al.

    J. Chromatogr. B

    (2012)
  • S. Liu et al.

    J. Biol. Chem.

    (2012)
  • L. Zhao et al.

    Bioorg. Med. Chem. Lett.

    (2013)
  • R.S. Barkowski et al.

    Cardiol. Rev.

    (2008)
  • H. Okamoto et al.

    Nature

    (2000)
  • Cited by (10)

    View all citing articles on Scopus
    View full text