Structural modification of 4, 5-dihydro-[1, 2, 4] triazolo [4, 3-f] pteridine derivatives as BRD4 inhibitors using
Jian-Bo Tong1,2, Ding Luo3,4, Yi Feng3,4
1College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, China. jianbotong@aliyun.com.
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: [Formula: see text] = 0.574, [Formula: see text] = 0.947) model, comparative molecular similarity index analysis (CoMSIA: [Formula: see text]= 0.622, [Formula: see text] = 0.916) model, topomer CoMFA ([Formula: see text] = 0.691, [Formula: see text]= 0.912) model and hologram quantitative structure-activity relationship (HQSAR: [Formula: see text]= 0.759, [Formula: see text] = 0.963) model. They show quite good external predictive power for the test set, with [Formula: see text] 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.
Insights
Researchers developed quantitative structure-activity relationship (QSAR) models to understand how small molecule inhibitors target BRD4 protein, a key factor in many cancers. These models guide the design of more effective BRD4 inhibitors for cancer treatment.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Oncology
Background:
- Cancer remains a critical global health challenge.
- Bromodomain 4 (BRD4) protein overexpression is linked to various malignant tumors.
- Developing small molecule BRD4 inhibitors is a significant area of medical research.
Purpose of the Study:
- To establish robust 3D/2D-QSAR models for 4,5-dihydro-[1, 2, 4] triazolo [4, 3-f] pteridine derivatives.
- To elucidate the relationship between chemical structure and inhibitory activity against BRD4.
- To guide the design of novel, potent BRD4 inhibitors.
Main Methods:
- Development of four quantitative structure-activity relationship (QSAR) models: Comparative Molecular Field Analysis (CoMFA), Comparative Molecular Similarity Index Analysis (CoMSIA), Topomer CoMFA, and Hologram Quantitative Structure-Activity Relationship (HQSAR).
- Validation of models using external test sets to assess predictive power.
- Integration of 2D/3D-QSAR results with molecular docking analyses.
- Design and potential verification of novel compounds based on model insights.
Main Results:
- Four QSAR models (CoMFA, CoMSIA, Topomer CoMFA, HQSAR) were successfully established with high statistical significance (R² values ranging from 0.574 to 0.759).
- All models demonstrated strong external predictive capabilities (Q² values ranging from 0.602 to 0.750).
- Analysis of contour maps and docking results provided insights into structural modifications for enhanced inhibitory activity.
Conclusions:
- The developed QSAR models effectively correlate structural features with BRD4 inhibitory activity.
- These findings provide a valuable framework for optimizing existing BRD4 inhibitor scaffolds.
- The study offers a reference for the rational design of new and improved BRD4-targeting anticancer agents.
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