Ligand-based drug design of quinazolin-4(3H)-ones as breast cancer inhibitors using QSAR modeling, molecular docking, and pharmacological profiling.

Background: Breast cancer is the most common tumor among females globally. Its prevalence is growing around the world, and it is alleged to be the leading cause of cancer death. Approved anti-breast cancer drugs display several side effects and resistance during the early treatment stage. Hence, there is a need for the development of more effective and safer drugs. This research was aimed at designing more potent quinazolin-4(3H)-one molecules as breast cancer inhibitors using a ligand-based design approach, studying their modes of interaction with the target enzyme using molecular docking simulation, and predicting their pharmacological properties.

Methods: The QSAR model was developed using a series of quinazoline-4(3H)-one derivatives by utilizing Material Studio v8.0 software and validated both internally and externally. Applicability domain virtual screening was utilized in selecting the template molecule, which was structurally modified to design more potent molecules. The inhibitive capacities of the design molecules were predicted using the developed model. Furthermore, molecular docking was performed with the EGFR target active site residues, which were obtained from the protein data bank online server (PDB ID: 2ITO) using Molegro Virtual Docker (MVD) software. SwissADME and pkCSM online sites were utilized in predicting the pharmacological properties of the designed molecules.

Results: Four QSAR models were generated, and the first model was selected due to its excellent internal and external statistical parameters as follows: R² = 0.919, R²_adj = 0.898, Q²_cv = 0.819, and R²_pred = 0.7907. The robustness of the model was also confirmed by the result of the Y-scrambling test performed with cR²p = 0.7049. The selected model was employed to design seven molecules, with compound 4 (pIC₅₀ = 5.18) adopted as the template. All the designed compounds exhibit better activities ranging from pIC₅₀ = 5.43 to 5.91 compared to the template and Doruxybucin (pIC₅₀ = 5.35). The results of molecular docking revealed better binding with the EGFR target compared with the template and Doruxybucin. The designed compounds exhibit encouraging therapeutic applicability, as evidenced by the findings of pharmacological property prediction.

Conclusions: The designed derivatives could be utilized as novel anti-breast cancer agents.