Target based structural optimization of substituted pyrazolopyrimidine analogues as inhibitor for IRAK4 by 3D-QSAR and molecular simulation

3D-QSAR models were established using 52 compounds of pyrazolopyrimidine analogues with multiple substituents. We studied the relationship between molecular structure and inhibitory activity using comparative molecular field analysis (CoMFA), CoMFA region focusing (CoMFA-RG), and comparative molecular similarity index (CoMSIA). The results showed the model established by CoMFA-RG method was the optimal model, and its internal cross-validation correlation coefficient ( q 2 = 0.703) and non-cross-validation correlation coefficient ( r 2 = 0.981) had good statistical significance. Ten newly designed compounds were designed and their ADME/T properties were tested based on contour maps. Molecular docking method was used to analyze the interaction between compound 31 and IRAK4. At the same time, it also showed the binding mode of the new compounds to IRAK4 was the same as the compound 31; the hydrogen bond and hydrophobic bond played important roles in the binding process. Molecular dynamics simulation results showed residues Met192, Tyr262, Met265, Asp278, and Ala315 played vital roles of compounds to IRAK4. Combined DFT and free energy analysis theoretically proved compound Des07 had higher inhibitory activity than compound 31.