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Structural determinants of benzodiazepinedione/peptide-based p53-HDM2 inhibitors using 3D-QSAR, docking and molecular dynamics

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Abstract

As a tumor suppressor, p53 protein regulates the cell cycle and is involved in preventing tumorgenesis. The protein level of p53 is under the tight control of its negative regulator human double minute 2 (HDM2) via ubiquitination. Therefore, the design of inhibitors of HDM2 has attracted much interest of research on developing novel anticancer drugs. Presently, two classes of molecules, i.e., the 1,4-benzodiazepine-2,5-diones (BDPs) and N-Acylpolyamine (NAPA) derivatives were studied by three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling approaches including the comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) as promising p53-HDM2 inhibitors. Based on both the ligand-based and receptor-guided (docking) alignments, two optimal 3D-QSAR models were obtained with good predictive power of q 2 = 0.41, r 2 pred = 0.60 for BDPs, and q 2 = 0.414, r 2 pred = 0.69 for NAPA analogs, respectively. By analysis of the model and its related contour maps, it is revealed that the electrostatic interactions contributed much larger to the compound binding affinity than the steric effects. And the contour maps intuitively suggested where to modify the molecular structures in order to improve the binding affinity. In addition, molecular dynamics simulation (MD) study was also carried out on the dataset with purpose of exploring the detailed binding modes of ligand in the HDM2 binding pocket. Based on the CoMFA contour maps and MD-based docking analyses, some key structural aspects responsible for inhibitory activity of these two classes of compounds were concluded as follows: For BDPs, the R1 and R3 regions should have small electronegativity groups; substituents R2 and R4 should be larger, and R3 substituent mainly involves in H-bonds forming. For NAPA derivatives, bulky and electropositive groups in ring B and ring A, small substituent at region P is favorable for the inhibitory activity. The models and related information, we hope, may provide important insight into the inhibitor-p53-HDM2 interactions and be helpful for facilitating the design of novel potent inhibitors.

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Acknowledgments

The research is supported by high-performance computing platform of Northwest A & F University. The research is financially supported by the Fund of Northwest A & F University. The authors are grateful to Prof. L. Yang for access of Sybyl software.

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Authors and Affiliations

  1. Bioinformatics Center, Northwest A&F University, Yangling, Shaanxi, 712100, China

    Fangfang Wang, Zhi Ma, Xia Wang & Yonghua Wang

  2. School of Chemical Engineering, Dalian University of Technology, Dalian, Liaoning, 116024, China

    Yan Li

  3. College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, 712100, China

    Yonghua Wang

Authors
  1. Fangfang Wang
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  2. Yan Li
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  3. Zhi Ma
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  4. Xia Wang
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  5. Yonghua Wang
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Corresponding author

Correspondence to Yonghua Wang.

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Wang, F., Li, Y., Ma, Z. et al. Structural determinants of benzodiazepinedione/peptide-based p53-HDM2 inhibitors using 3D-QSAR, docking and molecular dynamics. J Mol Model 18, 295–306 (2012). https://doi.org/10.1007/s00894-011-1041-4

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  • DOI: https://doi.org/10.1007/s00894-011-1041-4

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