Abstract
Interleukin-1 receptor-associated kinase 4 (IRAK-4) plays a pivotal role in signaling cascades associated with the immune and inflammatory diseases. Regulation of IRAK-4 is an attractive approach to treating related diseases. Herein, ligand-based pharmacophore model and atom-based 3D-QSAR studies have been carried out on 92 known ATP competitive inhibitors to IRAK-4. Fourpoint pharmacophore hypotheses with one hydrogen acceptor (A), one hydrogen donor (D), and two aromatic rings (R) were developed by PHASE module of Schrödinger suit. The best pharmacophore hypothesis was selected on the basis of good PLS statistics (R2 train = 0.9806, Q2 test = 0.7182, Pearson- R = 0.8767, SD = 0.2248, RMSE=0.3152, F= 637.2). Furthermore, a series of virtual screening were performed and the Prime/MM-GBSA method based on the docking complex was used to predict the binding-free energy. Finally, 12 hits were identified as potent and novel IRAK-4 inhibitors. We mainly analyzed the binding modes and binding energies of the candidate compounds with the scaffolds of anthraquinones and 9-fluorenones. The result of virtual screening was further validated using molecular dynamics (MD) simulation analysis. A 10 ns MD simulation analysis revealed high stability and effective binding of ZINC09047206, ZINC12885209 within the active site of IRAK-4. It turned out that the anthraquinones hit ZINC09047206 and ZINC09477176 have more effective IRAK-4 inhibitory potential than those of other obtained hits.
Keywords: IRAK-4 inhibitors, pharmacophore model, 3D-QSAR, MM-GBSA, molecular dynamics simulation.
Graphical Abstract
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