Computational Studies of Novel Aniline Pyrimidine WDR5‐MLL1 Inhibitors: QSAR, Molecular Docking, and Molecular Dynamics Simulation

WD repeat‐containing protein 5 (WDR5) and mixed lineage leukemia (MLL) are critical for maintaining tumorigenesis in human cancers. Disruption of the MLL1–WDR5 interaction has been viewed as a promising therapeutic strategy for the treatment of leukemia. Here, we report a series of protein–protein binding interaction modes targeting MLL1‐WDR5 inhibitors using 3D‐QSAR, and molecular docking. CoMFA with q 2 = 0.724, r 2 = 0.957, r pred 2 = 0.874 and CoMSIA with q 2 = 0.826, r 2 = 0.995, r pred 2 = 0.827. Topomer CoMFA results show q 2 = 0.807, r 2 = 0.976, r pred 2 = 0.789, and HQSAR results show q 2 = 0.873, r 2 = 0.982, r pred 2 = 0.794. The 3D‐QSAR model with high validation and prediction performance is successfully constructed. Contour maps and molecular docking results according to the four models, 26 new compounds are finally designed on the computer after molecular screening. Further molecular dynamics simulations (MD) of compounds G01, G04, G09, G43, and G44 with high predicted activity are carried out to explore their possible binding modes. ILE305, PHE133, CYS261, and ALA176 are found to play crucial roles in stabilizing the inhibitor. ADMET predictions are also performed for these 26 new compounds. These results serve as references for the design of effective WDR5‐MLL1 inhibitors in the future.