Discovery of potent IRAK-4 inhibitors as potential anti-inflammatory and anticancer agents using structure-based exploration of IRAK-4 pharmacophoric space coupled with QSAR analyses

Computational Biology and Chemistry
Mohammad A Khanfar, Saja Alqtaishat

Abstract

Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) has an important role in immunity, inflammation, and malignancy. The significant role of IRAK-4 makes it an interesting target for the discovery and development of potent small molecule inhibitors. In the current study, multiple linear regression -based QSAR analyses coupled with structure-based pharmacophoric exploration was applied to reveal the structural and physiochemical properties required for IRAK-4 inhibition. Manually built pharmacophoric models were initially validated with receiver operating characteristic curve, and best-ranked models were subsequently integrated in QSAR analysis along with other physiochemical descriptors. The pharmacophore model, selected using the statistically optimum QSAR equation, was implied as a 3D-search filter to mine the National Cancer Institute database for novel IRAK-4 inhibitors. Whereas the associated QSAR model prioritized the bioactivities of captured hits for in vitro evaluation. Experimental validation identified several potent IRAK-4 inhibitors of novel structural scaffolds. The most potent captured hit exhibited an IC50 value of 157 nM.

Citations

Feb 9, 2020·Nature Reviews. Rheumatology·Eva Schrezenmeier, Thomas Dörner

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