Targeting CDK4/6 in Cancer: Molecular Docking and Cytotoxic Evaluation of Thottea siliquosa Root Extract.

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) are pivotal regulators of the cell cycle, whose dysregulation is closely linked to cancer progression. While synthetic CDK4/6 inhibitors such as Palbociclib and Ribociclib are clinically effective, their use is limited by significant adverse effects. Methods: In this study, the aqueous root extract of Thottea siliquosa, a traditionally used medicinal plant, was evaluated for its potential as a natural CDK4/6 inhibitor. Phytochemical profiling using GC-MS identified bioactive compounds, which were subsequently subjected to molecular docking, ADME prediction, and in vitro cell-based assays using HCT116 and L929 cells. Results: The docking results revealed that Isocorydine (-7.4 kcal/mol for CDK4 and -7.2 kcal/mol for CDK6) and Thunbergol (-6.5 kcal/mol for CDK4 and -7.0 kcal/mol for CDK6) exhibited promising binding affinities comparable to standard CDK inhibitors, Palbociclib (-7.2, -8.3 kcal/mol) and Ribociclib (-7.1, -8.1 kcal/mol). Among the other tested natural compounds, Squalene (-7.1 kcal/mol for CDK4) and 2-palmitoylglycerol (-5.2 kcal/mol for CDK4, -4.9 kcal/mol for CDK6) demonstrated moderate binding affinities. ADME analysis confirmed favorable drug-like properties with minimal toxicity alerts. The extract displayed dose-dependent cytotoxicity with an IC(50) of 140 μg/mL and reduced cell migration in HCT116 cells, indicating potential anti-proliferative effects. These findings suggest that T. siliquosa root extract, through synergistic phytochemical interactions, holds promise as a multi-targeted, plant-based therapeutic candidate for CDK4/6-associated cancers, warranting further in vitro and in vivo validation.