Novel design and in silico optimization of 5-azaquinazoline-based IRAK4 inhibitors using qsar, docking, pharmacokinetics, and molecular dynamics for diffuse large B-Cell lymphoma

• A validated QSAR model (R² = 0.83, Q² = 0.74) was developed for 5-azaquinazoline-based IRAK4 inhibitors. • Compound 15 was optimized via ligand-based design to yield derivative 15b. • Compound 15b showed strong binding affinity (–11.5 kcal/mol) and high predicted potency. • ADMET analysis confirmed favourable absorption, drug-likeness, and non-mutagenicity. • MD simulations and MM-GBSA (–84.52 kcal/mol) confirmed stable and enhanced protein–ligand binding. • Compound 15b is proposed as a promising candidate for DLBCL-targeted therapy. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a pivotal node in the MYD88–NF-κB signalling cascade, often dysregulated in diffuse large B-cell lymphoma (DLBCL). In this study, a series of 5-azaquinazoline derivatives were evaluated as potential IRAK4 inhibitors using a fully integrated computational workflow. A statistically robust QSAR model (R² = 0.83, Q²_LOO = 0.74, CCC = 0.86) identified four key descriptors influencing bioactivity, offering interpretability and strong predictive reliability. Molecular docking revealed Compound 15 as a lead candidate with a binding affinity of –9.7 kcal/mol and high predicted potency. Scaffold optimization yielded Compound 15b, which surpassed the reference inhibitor ND-2158 in binding strength (–11.5 kcal/mol), drug-likeness, and synthetic accessibility. ADMET predictions confirmed favourable absorption, metabolic stability, and non-mutagenicity. Molecular dynamics simulations over 100 ns demonstrated stable protein-ligand interactions, while MM-GBSA binding free energy calculations validated its enhanced affinity (–84.52 kcal/mol vs. –57.86 kcal/mol for ND-2158). These results position Compound 15b as a promising 5-azaquinazoline-based IRAK4 inhibitor with potential for further development in DLBCL therapy.