Design of novel PLK4 inhibitors as TRIM37-amplified breast cancer drugs using 3D-QSAR, molecular docking, and molecular dynamics simulation methods

A mitosis-associated protein kinase, serine/threonine protein kinase polo-like kinase 4 (PLK4) is thought to be a promising target for the therapy of tripartite motif-containing 37 (TRIM37)-amplified breast cancer. The study's dataset for 3D-QSAR modelling included 37 derivatives of pyrazolo3,4-d pyrimidines, and the outcomes showed strong statistical significance (COMFA: q2 = 0.744, r2 = 0.997, rpred2 = 0.702; CoMSIA: q2 = 0.652, r2 = 0.991, rpred2 = 0.722). Findings from an analysis of isopotential maps using the COMFA and COMSIA models, ten novel small molecule inhibitors with potentially high activities were designed. To investigate the processes of interactions among the inhibitor molecules along with the receptor proteins, molecular docking and simulations of molecular dynamics were utilised. According to the results, the amino acids Cys92, Glu96, Asn94, and Asn103 may form hydrogen bonds with the ligands, which could enhance the small molecules' inhibitory effect. Furthermore, MMPBSA calculations revealed that the newly created compounds have a higher binding affinity to the receptor proteins. Ultimately, these compounds also demonstrated good AMDET properties in pharmacokinetic parameter tests, indicating their promise as innovative medications for the management of breast cancer. These results offer the theoretical direction required to support the creation of effective PLK4 inhibitors.