Design of Novel IRAK4 Inhibitors Using Molecular Docking, Dynamics Simulation and 3D-QSAR Studies.

Treatment of several autoimmune diseases and types of cancer has been an intense area of research over the past two decades. Many signaling pathways that regulate innate and/or adaptive immunity, as well as those that induce overexpression or mutation of protein kinases, have been targeted for drug discovery. One of the serine/threonine kinases, Interleukin-1 Receptor Associated Kinase 4 (IRAK4) regulates signaling through various Toll-like receptors (TLRs) and interleukin-1 receptor (IL1R). It controls diverse cellular processes including inflammation, apoptosis, and cellular differentiation. MyD88 gain-of-function mutations or overexpression of IRAK4 has been implicated in various types of malignancies such as Waldenström macroglobulinemia, B cell lymphoma, colorectal cancer, pancreatic ductal adenocarcinoma, breast cancer, etc. Moreover, over activation of IRAK4 is also associated with several autoimmune diseases. The significant role of IRAK4 makes it an interesting target for the discovery and development of potent small molecule inhibitors. A few potent IRAK4 inhibitors such as PF-06650833, RA9 and BAY1834845 have recently entered phase I/II clinical trial studies. Nevertheless, there is still a need of selective inhibitors for the treatment of cancer and various autoimmune diseases. A great need for the same intrigued us to perform molecular modeling studies on 4,6-diaminonicotinamide derivatives as IRAK4 inhibitors. We performed molecular docking and dynamics simulation of 50 ns for one of the most active compounds of the dataset. We also carried out MM-PBSA binding free energy calculation to identify the active site residues, interactions of which are contributing to the total binding energy. The final 50 ns conformation of the most active compound was selected to perform dataset alignment in a 3D-QSAR study. Generated RF-CoMFA (