A Computational approach to discover potential quinazoline derivatives against CDK4/6 kinase

Abstract

CDK is a protein (serine-threonine) kinase family that plays an important role in the cell cycle and oncogenic transformation processes. This controls the activity of an enzyme involved in cell proliferation in response to endogenous and exogenous signals. Quinazoline derivatives are essential components in the inhibition or destruction of cancer cell processes such as breast cancer. The current research entails the development of pharmacophore models, 3-D-QSAR, virtual screening, and docking studies, with evaluation by different parameters. A total of 46 ligands were chosen for the analysis, yielding ADRRR_1 as the best pharmacophore model with a survival score of 5.48. The 3D QSAR study showed significant model with R2 =0.98 and Q2 = 0.55. The series top-scoring compound was 4a with a docking score of -13.62 and showed interactions with the amino acids LYS-43, GLU-61, and VAL-101. The developed pharmacophore model was used to screen ZINC compounds, that were further screened by using a virtual screening study. The compounds ZINC75260693, ZINC68584027, ZINC20411715, ZINC08928348, and ZINC11964703 showing the highest XP docking scores (-10.71, -10.60, -10.51, -9.86, -9.83, consecutively). The compound with the highest score, ZINC75260693, showed binding interactions with VAL-101, PHE-98, LYS-43, GLU-61, and ASP-163 (PDB ID: 2EUF). The compounds' drug-like properties were revealed through ADME study. The findings of this study may aid in the production of quinazoline derivatives that target CDK4/6 kinase in the future.