In Silico Screening and Molecular Dynamics Simulation of Leucas aspera Bioactive Compounds: Computational Identification of Novel AMPKα2 Inhibitors for Cancer Therapy

Cancer remains a leading cause of global mortality, necessitating novel therapeutic approaches targeting cellular energy metabolism pathways. This study investigated bioactive compounds from Leucas aspera as potential AMPK a2 inhibitors for cancer therapy through comprehensive in silico analysis. Gas chromatography-mass spectrometry (GC–MS) analysis identified 19 phytochemical compounds from methanolic extract of L. aspera. Following bioactive filtering using Lipinski's Rule of Five, compounds LA2, LA3, LA4, LA5, LA6, LA7, LA8, LA9, LA12, and LA18 demonstrated drug-likeness properties. ADMET prediction revealed that LA2, LA3, LA4, LA5, LA6, LA7, LA12, and LA18 exhibited high solubility levels, while most compounds showed favorable blood-brain barrier permeability except LA1, LA10, LA11, LA13, LA14, LA15, LA16, LA17, and LA19. Molecular dynamics simulations over 100 ns demonstrated structural stability with RMSD values ranging from 0.3 Å to 2.4 Å. Molecular docking identified LA11, LA15, and LA16 as the top-performing compounds, with MolDock scores of 118.3 to 117.0 and Re-rank scores between 99.8 and 96.4, indicating favourable interactions with AMPKa2. The reference ligand, TAK_1, displayed a substantially stronger MolDock score of 138.3, underscoring that while the phytochemicals exhibit measurable binding affinity, they are less potent than the benchmark inhibitor. These compounds are therefore proposed as promising lead scaffolds for further optimisation rather than direct therapeutic candidates.