Computational insights into thiourea derivatives and their copper complexes as potential CDK inhibitors in HCT116 colon carcinoma cells

N-Acylthiourea derivatives bearing a piperazinyl group are valuable anticancer scaffolds due to their structural versatility, favorable physicochemical properties, and ability to interact with multiple cancer-related biological targets. They are considered promising leads for developing new chemotherapeutic agents. In this study, ten ligands were synthesized in our laboratory and evaluated for their cytotoxic activity against HCT116 colon carcinoma cells. Building on these findings, we designed and computationally modeled novel copper(I) complexes of the ligands as potential inhibitors of cyclin-dependent kinase 2 (CDK2), a well-established therapeutic target in colorectal cancer. A comprehensive in silico approach was employed, including molecular docking, ADMET prediction, and drug-likeness evaluation. The ligands and their copper(I) complexes were docked against the CDK2 crystal structure (PDB ID: 2VTO), and binding affinities were assessed. Before docking, all compounds were geometry optimized, and their electronic properties, such as total energy and HOMO/LUMO orbital distributions, were calculated to inform docking simulations. ProTox 3.0 predicted all compounds to be non-toxic across major endpoints, with inactivity probabilities ranging from 0.50 to 0.99. The results suggest that both the free ligands and their copper complexes exhibit favorable binding interactions with the CDK2 active site, supporting their potential as lead compounds for further development in colon cancer therapeutics. Molecular dynamics simulations using the selected OPLS-AA force field were performed to analyze RMSD, RMSF, and protein–ligand contacts for the best docking poses.