Integrated QSAR, docking, pharmacokinetics, and molecular dynamics approaches for designing IRAK4 inhibitors against MYD88L265P-driven diffuse large B-cell lymphoma

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key mediator of MYD88L265P-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, Q²LOO = 0. 5982, and CCC = 0. 7748 and showed good external predictability (RMSEₜest = 0. 4441, CCCₜest = 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 ΔGbind = − 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.