Design and in silico evaluation of quinazoline derivatives for hepatic cancer: QSAR modeling, ADMET profiling, molecular docking, and dynamics simulations

This study focuses on the development of a quantitative structure-activity relationship (QSAR) model to predict the anticancer activity of quinazoline-based compounds, specifically targeting hepatic cancer (HepG2 cells). A dataset of 35 quinazoline derivatives with known anticancer activity was sourced from the literature. The compound structures were constructed using ChemDraw, and energy minimization was performed using the MM2 force field in Chem3D Pro. Molecular descriptors were calculated (1800 descriptors) using PaDEL Descriptor software, and QSAR modeling was conducted using QSARINS software. The dataset, including IC 50 values, was divided into a training set (80%) and a test set (20%). Two QSAR models were developed: Model 1 demonstrated a high performance with an R 2 value of 0.9671 and an adjusted R 2 of 0.9600, while Model 2, selected as the optimal model, exhibited a stronger correlation (R 2 = 0.9763, adjusted R 2 = 0.9706) and minimal overfitting (Friedman’s lack of fit = 0.0185). Both models were validated through internal and external tests, including Leave-One-Out (LOO) and Leave-Many-Out (LMO) cross-validation, Y-scrambling, and applicability domain analysis. Model 2 showed excellent predictive accuracy, with key descriptors such as ATSC4m, AATSC7i, and GATS5c significantly influencing the biological activity predictions. Based on the best-performing QSAR model and SAR studies, 35 novel compounds ( AA1 - AA35 ) were designed, and their pIC 50 values were predicted. The top 15 compounds were further evaluated through docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis, and MD simulations. AA19 showed the best binding affinity (-8.30 kcal/mol), forming stable hydrogen bonds with ASP86, LEU83, and GLU12, and Pi-alkyl interactions with VAL18, ALA144, and LEU134. The complex remained stable, with protein RMSD between 1.75-2.0 Å and ligand RMSD starting at 1.2 Å. RMSF values remained below 2.4 Å, indicating minimal residue fluctuation.