Integrated QSAR, docking, pharmacokinetics, and molecular dynamics approaches for designing IRAK4 inhibitors against MYD88^L265P-driven diffuse large B-cell lymphoma

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key mediator of MYD88^L265P-driven diffuse large B-cell lymphoma (DLBCL) and a promising drug target. We applied an integrated in silico pipeline, namely, 2D-QSAR (MLR with GA), molecular docking, ADMET profiling, and 100-ns molecular dynamics, to prioritize pyrrolopyrimidine-based IRAK4 inhibitors. The final 2D-QSAR model achieved R² = 0.7279, Q²_LOO = 0.5982, and CCC = 0.7748 and showed good external predictability (RMSE_test = 0.4441, CCC_test = 0.6934). Docking identified compound 15 (− 10.1 kcal·mol⁻¹) and its optimized analogue 15c (− 10.3 kcal·mol⁻¹) as the top binders. Compound 15c exhibited strong binding (MM-GBSA ΔG_bind = − 66.41 kcal·mol⁻¹ vs. − 57.86 kcal·mol⁻¹ for ND-2158), high predicted intestinal absorption (~ 91.6%), and AMES-negative status; 100-ns MD confirmed a stable binding pose. While experimental validation is needed, compound 15c is prioritized as a promising lead for MYD88-mutant DLBCL.