Computational identification of Cucurbitacin S and Kammogenin as bioactive focal adhesion kinase 2 inhibitors for targeted cancer therapy.

Focal adhesion kinase 2 (FAK2) is a non-receptor tyrosine kinase that orchestrates key oncogenic processes, including cell adhesion, migration, proliferation, and survival, and is frequently overexpressed in multiple cancer types. Targeting its ATP-binding and active sites has emerged as a promising therapeutic approach. Here, we performed a systematic virtual screening of 11,699 phytoconstituents from the Indian medicinal plants to identify potent FAK2 inhibitors. Docking analysis shortlisted top candidates based on binding affinity, followed by pharmacokinetic profiling (ADMET) and biological activity prediction (PASS). Two compounds, Cucurbitacin S and Kammogenin, exhibited strong binding affinities (- 9.5 and - 9.3 kcal/mol) and favorable ADMET properties, with predicted anticancer and anti-inflammatory activities. Detailed interaction studies revealed stable binding to critical residues, including Asp549 in the active site. Molecular dynamics simulation for 300 ns confirmed the stability and compactness of FAK2-compound complexes, with minimal structural perturbation. Essential dynamics analyses indicated reduced conformational flexibility upon ligand binding, while MM-PBSA calculations demonstrated favorable binding free energies. A comparative analysis with the reference inhibitor PF-562271 indicated the therapeutic potential of both phytochemicals, pending experimental evaluation. These findings suggest that Cucurbitacin S and Kammogenin are promising lead scaffolds for the development of plant-derived FAK2 inhibitors; however, as this is a computational, hypothesis-generating study, the results warrant further experimental validation to confirm their therapeutic potential.