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

ABSTRACT

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 pyrazolo[3,4-d] pyrimidines, and the outcomes showed strong statistical significance (COMFA: q²=  0.744, r²=  0.997, $r_{\mathrm{pred}}^2$= 0.702; CoMSIA: q²= 0.652, r² = 0.991, $r_{\mathrm{pred}}^2$= 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.

KEYWORDS:

• Serine/threonine-protein kinase polo-like kinase 4 inhibitor
• 3D-QSAR
• Molecular docking
• Molecular dynamics
• ADMET properties

Author contributions

All authors contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by Yinyin Zhan. The first draft of the manuscript was written by Yinyin Zhan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosure statement

No potential conflict of interest was reported by the author(s).