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

Area of Science:

• Pharmacology
• Natural Products Chemistry
• Cancer Biology

Background:

• Cyclin-dependent kinases 4 and 6 (CDK4/6) are key cell cycle regulators implicated in cancer progression.
• Current synthetic CDK4/6 inhibitors (e.g., Palbociclib, Ribociclib) have significant adverse effects, necessitating alternative therapeutic strategies.

Purpose of the Study:

• To investigate the potential of the aqueous root extract of *Thottea siliquosa* as a natural inhibitor of CDK4/6.
• To identify bioactive compounds within the extract and evaluate their inhibitory effects on CDK4/6.

Main Methods:

• Phytochemical profiling of *Thottea siliquosa* root extract using Gas Chromatography-Mass Spectrometry (GC-MS).
• Molecular docking simulations to assess binding affinities of identified compounds to CDK4 and CDK6.
• Absorption, Distribution, Metabolism, and Excretion (ADME) prediction and in vitro cell-based assays (cytotoxicity, cell migration) using HCT116 and L929 cells.

Main Results:

• Isocorydine and Thunbergol exhibited strong binding affinities to CDK4/6, comparable to Palbociclib and Ribociclib.
• Squalene and 2-palmitoylglycerol showed moderate binding affinities; ADME analysis predicted favorable drug-like properties with low toxicity.
• The extract demonstrated dose-dependent cytotoxicity (IC50 = 140 μg/mL) and reduced HCT116 cell migration, indicating anti-proliferative activity.

Conclusions:

• The *Thottea siliquosa* root extract contains phytochemicals, such as Isocorydine and Thunbergol, with significant CDK4/6 inhibitory potential.
• The extract exhibits promising anti-proliferative effects and favorable pharmacokinetic properties, suggesting its utility as a plant-based therapeutic candidate.
• Further in vitro and in vivo studies are warranted to validate the therapeutic potential of *Thottea siliquosa* for CDK4/6-associated cancers.