Structure‐based Pharmacophore Screening Coupled with QSAR Analysis Identified Potent Natural‐product‐derived IRAK‐4 Inhibitors
Mohammad A. Khanfar · Molecular Informatics · 2021
Abstract 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.