Identification of bioactive phytoconstituents as promising ABL2 inhibitors using virtual screening and molecular dynamics simulation

ABL proto-oncogene 2 (ABL2) is an essential nonreceptor tyrosine kinase that regulates cytoskeletal dynamics, cell adhesion, and migration. ABL2 is dysregulated in multiple cancers and represents a promising therapeutic target. However, currently available tyrosine kinase inhibitors are limited by drug resistance and off-target effects. In this study, a structure-based virtual screening approach was performed to identify bioactive phytoconstituents with potential ABL2 inhibitory activity. An initial virtual screening of 11,908 natural compounds from the IMPPAT-2 library was conducted using molecular docking, and the best hits were subsequently filtered based on physicochemical and pharmacokinetic profiles. The top two compounds, Pachyrrhizin and Lupinisoflavone K, showed appreciable binding affinity with appropriate pharmacokinetic properties. Molecular dynamics simulations confirmed stable interactions within the ABL2 binding pocket, supported by hydrogen bonding throughout the simulation, suggesting constant binding of Pachyrrhizin and Lupinisoflavone K with ABL2. The conformational dynamics of these protein-ligand complexes were further confirmed by principal component analysis and free-energy landscape analysis. Overall, the findings suggest that Pachyrrhizin and Lupinisoflavone K may serve as potential ABL2 inhibitors, warranting further in vitro and in vivo validation.