Exploring benzothiazole derivatives: Promising PLK1 Inhibitors for cancer therapy through Virtual screening, Molecular docking, and ADMET evaluation

Abstract

The search for effective cancer therapies has driven significant interest in targeting Polo-like kinase 1 (PLK1), a crucial regulator of cell cycle progression, mitosis, epithelial-mesenchymal transition, autophagy, and DNA replication. Over expression of PLK1 is frequently observed in various cancers, making it a promising therapeutic target. Given the need for novel and potent PLK1 inhibitors, this study investigates the benzothiazole-containing drug 5f-203, known for inducing cell cycle arrest, as a potential PLK1 inhibitor. Using the PubChem database, novel PLK1 inhibitors were identified with 5f-203 (clinical trial, Phase 1) as the reference molecule. A comprehensive computational approach, including virtual screening, ligand and protein preparation, grid building, and molecular docking, was employed to evaluate co-crystallized ligand 5f-203, screened molecules, and newly designed compounds (N1-N6). Protein validation using ProSA (-7.9), ERRAT (95.36%), and the Ramachandran plot (84.1% residues in favored regions) confirmed model reliability. Lipinski’s rule was applied as an additional filter, and molecular docking revealed binding affinity values ranging from -8.82 to -7.73 kcal/mol, with molecule P1 exhibiting the highest affinity (-8.82 kcal/mol). Interaction analysis showed that 5f-203 formed H-bonds with Arg120 and NH2, while Ala66, Arg122, and Ile118 contributed to pi-alkyl interactions. Newly designed compounds (N1-N6) outperformed 5f-203 in docking scores, with synthetic accessibility below 4.5. ADMET studies further supported their drug-like potential. These findings suggest that the top 10 screened hits and newly designed benzothiazole derivatives hold promise as PLK1 inhibitors, offering a potential avenue for cancer therapy.