QSAR, Molecular Docking, and Dynamics-Based Computational Discovery of Potential PLK4 Inhibitors Against Tumor

Abstract

PLK4(polo-like kinase 4), an enzyme regulating centrioles, has been identified as a highly promising target for cancer treatment, making the development of PLK4 inhibitors crucial for advancing cancer therapy. In this study, 26 PLK4 inhibitors based on the imidazo[3,4-d]pyrimidine scaffold, exhibiting anti-tumor activity, were selected. Reliable 3D/2D-QSAR models, Topomer CoMFA ([[EQUATION]]=0.618, [[EQUATION]]=0.965), and HQSAR ([[EQUATION]]=0.711, [[EQUATION]]=0.862), were established, demonstrating excellent internal and external predictive abilities and reliable applicability domains. Using the 3D/2D-QSAR models, nine PLK4 inhibitors with high theoretical activity were designed, and subsequent molecular docking and molecular dynamics studies revealed strong interactions between the new compounds and the receptor protein, particularly hydrophobic interactions. This research provides a robust screening model for the development of PLK4 inhibitors, offering valuable insights into the design of potential solutions to clinical challenges associated with PLK4 inhibitors.

Keywords: polo-like kinase 4, 3D/2D-QSAR, molecular docking, molecular dynamics, ADMET