Investigation of ABL Kinase Inhibitory Potential of Bioactive From Juglans Regia: Molecular Docking, Pharmacophore Modelling and Molecular Dynamics Simulation Study

Abstract

Objective: The present study aimed to investigate the potential of phytoconstituents of Juglans regia derived from IMPPAT database as inhibitors of the Abelson tyrosine kinase (c-Abl), using in silico tools. Methods: Physicochemical and pharmacokinetic properties were predicted using QikProp, while toxicity profiles were evaluated with admetSAR. The molecular docking was performed against c-Abl kinase (PDB ID: 2HYY), followed by MM-GBSA binding free energy calculations. Pharmacophore modelling identified key interaction features, and 100 ns molecular dynamics (MD) simulations assessed complex stability. Prediction of Activity Spectra for Substances (PASS) prediction was used to predict potential biological activities. Results: Most phytoconstituents exhibit favourable drug-likeness and oral bioavailability with acceptable pharmacokinetic and low predicted toxicity. Molecular docking analysis identified plumbagin as the potential compound among phytoconstituents, exhibiting a docking score of −10.27 kcal/mol. Plumbagin showed predicted interactions including hydrogen bonding, hydrophobic interactions, and π–π stacking. Binding free energy calculations further supported the stability of the complex. Pharmacophore modelling highlighted the hydroxyl group and aromatic naphthoquinone scaffold as key features responsible for ligand binding. Molecular dynamics (MD) simulations demonstrated the ligand exhibited positional deviations within the binding pocket, indicating dynamic binding behaviour. PASS prediction predicted that plumbagin may possess neuroprotective effects, including antioxidant, anti-inflammatory, and cytoprotective effects. Conclusion: The findings identify plumbagin as a candidate for c-Abl kinase inhibitor. However, further in vitro and in vivo studies are required to validate its efficacy and safety.