Computational discovery of novel anticancer agents: A comprehensive study of phenothiazine derivatives

Cancer remains a major global health challenge due to uncontrolled cell proliferation and metastasis. This study aimed to investigate 14 newly synthesized phenothiazine derivatives as potential anticancer agents, focusing on cyclin-dependent kinase 2 (CDK2, PDB: 1CKP) and aromatase (PDB: 4KQ8) as therapeutic targets. A comprehensive computational strategy was applied, including density functional theory (DFT) calculations at B3LYP/6-31G(d,p) in gas phase, molecular docking using docking engine AutoDock Vina, molecular dynamics (MD) simulations for 100 ns, binding force analyses, drug-likeness and ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions, and frontier molecular orbital (FMO) (highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO)) assessments. Standard anticancer agents, tamoxifen, doxorubicin, letrozole, and flavopiridol, were used for comparative evaluation. Among the derivatives, compound 3 (targeting aromatase with a docking score of −10.0 kcal∙mol⁻ 1 .) and compound 12 (targeting CDK2 with −10.9 kcal∙mol⁻ 1 docking score) showed the strongest binding affinities, often comparable to or exceeding those of the reference drugs. Both exhibited interaction patterns similar to tamoxifen with CDK2 and BRD4, supporting their potential as multitarget anticancer agents. All synthesized molecules fulfilled drug-likeness criteria and demonstrated mild to moderate predicted oral toxicity, appearing to possess characteristics that could support oral administration and need further investigation. Broader screening against six additional cancer-related proteins, including glucose-6-phosphate dehydrogenase (G6PD, PDB: 4D7B), aryl hydrocarbon receptor ligand-binding domain (AHR-LBD, PDB: 5D0R), glucose-regulated protein 78 (GRP78, PDB: 5F1X), and the SCF complex (PDB: 1FQV), further highlighted their therapeutic promise. This integrated computational analysis identified derivatives 3 and 12 as promising phenothiazine-based anticancer candidates with favorable drug-likeness, acceptable toxicity, and multitarget binding capacity. These findings provide a foundation for future in vivo and clinical investigations to validate their potential as inhibitors of CDK2, aromatase, and other cancer-associated proteins.