Identification of Pyrroloimidazoles as Potential Inhibitors of WDR5-WIN-Site by 3D-QSAR Molecular Simulation

WD repeat structural domain 5 (WDR5), which plays an important role in various biological functions through epigenetic regulation, is aberrantly expressed in human cancers, and is an effective target for the discovery of anticancer drugs. In this paper, QSAR modeling analysis, including comparative molecular field (CoMFA) and comparative molecular similarity index analysis field (CoMSIA), was first performed using 41 pyrroloimidazole analogs. The results showed q2=0.667 and r2=0.981 in CoMFA and q2=0.662 and r2=0.983 in CoMSIA. Molecular docking and molecular dynamics simulations further confirmed the interaction and binding affinity of the inhibitors with key residues of the proteins, for example, PHE149, PHE133, and CYS261. Based on QSAR and docking studies, seven new compounds with high scores and qualified ADMET performance were designed. In this study, new ideas have been provided for exploring new WDR5 inhibitors.