Structure-based Pharmacophore Screening Coupled with QSAR Analysis Identified Potent Natural-product-derived IRAK-4...

Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) has crucial functions in inflammation, innate immunity, and malignancy. Structure-based pharmacophore modeling integrated with validated QSAR analysis was implemented to discover structurally novel IRAK-4 inhibitors from natural products database. The QSAR model combined molecular descriptors with structure-based pharmacophore capable of explaining bioactivity variation of structurally diverse IRAK-4 inhibitors. Manually built pharmacophore model, validated with receiver operating characteristic curve, and selected using the statistically optimum QSAR equation, was applied as a 3D-search query to mine AnalytiCon Discovery database of natural products. Experimental in vitro testing of highest-ranked hits identified uvaretin, saucerneol, and salvianolic acid B as active IRAK-4 inhibitors with IC₅₀ values in low micromolar range.