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Structural modification of 4, 5-dihydro-[1, 2, 4] triazolo [4, 3-f] pteridine derivatives as BRD4 inhibitors using 2D/3D-QSAR and molecular docking analysis

Abstract

Cancer treatment continues to be one of the most serious public health issues in the world. The overexpression of BRD4 protein has led to a series of malignant tumors, hence the development of small molecule BRD4 protease inhibitors has always been a hot spot in the field of medical research. In this study, a series of 4,5-dihydro-[1, 2, 4] triazolo [4, 3-f] pteridine derivatives were used to establish 3D/2D-QSAR models and to discuss the relationship between inhibitor structure and activity. Four ideal models were established, including the comparative molecular field analysis (CoMFA: \({q}_{cv}^{2}\) = 0.574, \({r}_{ncv}^{2}\) = 0.947) model, comparative molecular similarity index analysis (CoMSIA: \({q}_{cv}^{2}\)= 0.622, \({r}_{ncv}^{2}\) = 0.916) model, topomer CoMFA (\({q}_{cv}^{2}\) = 0.691, \({r}_{ncv}^{2}\)= 0.912) model and hologram quantitative structure–activity relationship (HQSAR: \({q}_{cv}^{2}\)= 0.759, \({r}_{ncv}^{2}\) = 0.963) model. They show quite good external predictive power for the test set, with \({{r}_{ncv}^{2}}_{\mathrm{pred}}\) values of 0.602, 0.624, 0.671 and 0.750, respectively. In addition, the contour and color code map given by the 2D/3D-QSAR model with the results of molecular docking analyzed to chalk up modification methods for improving inhibitory activity, which was verified by designing novel compounds. The analysis results are helpful to promote the modification of the inhibitor framework and to provide a reference for the construction of new and promising BRD4 inhibitor compounds.

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Funding

This work was supported by the National Natural Science Funds of China (21475081), the Natural Science Foundation of Shaanxi Province of China (2019JM-237) and the Graduate Innovation Fund of Shaanxi University of Science and Technology.

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All authors contributed to the study conception and design. Material preparation, data collection were performed by Jian-Bo Tong, Ding Luo, Yi Feng, Shuai Bian, Xing Zhang and Tian-Hao Wang. Data analysis is were by performed by Jian-Bo Tong. The first draft of the manuscript was written by Ding Luo and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jian-Bo Tong.

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Tong, JB., Luo, D., Feng, Y. et al. Structural modification of 4, 5-dihydro-[1, 2, 4] triazolo [4, 3-f] pteridine derivatives as BRD4 inhibitors using 2D/3D-QSAR and molecular docking analysis. Mol Divers 25, 1855–1872 (2021). https://doi.org/10.1007/s11030-020-10172-5

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Keywords

  • 3D-QSAR
  • 2D-QSAR
  • Molecular docking
  • BRD4 inhibitors
  • Structural modification