Structure-based computational assessment of Bacopa monnieri-derived compounds as potential dual target anti-seizure...

Epilepsy remains a debilitating neurological disorder affecting approximately 50 million individuals worldwide. Current Anti-seizure medications (ASM) targeting Synaptic Vesicle Protein 2A (SV2A), such as levetiracetam, exhibit variable efficacy and adverse effect profiles, necessitating exploration of novel therapeutic approaches. This study investigates Bacopa monnieri-derived compounds as potential dual inhibitors of SV2A and Carbonic Anhydrase II (CA-II), two mechanistically distinct targets implicated in seizure pathophysiology. An integrated computational workflow comprising ADMET profiling, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations was implemented to evaluate selected phytoconstituents. ADMET analysis revealed favourable pharmacokinetic parameters for several compounds, particularly Ebelin Lactone and Jujubogenin, with superior blood-brain barrier permeability (BBB >0.9) and human intestinal absorption (>95 %) compared to reference drugs. Molecular docking identified compelling binding affinities, with Ebelin Lactone (-11.2 kcal/mol) and Jujubogenin (-10.9 kcal/mol) exhibiting stronger interactions with SV2A than brivaracetam (-6.8 kcal/mol). Similarly, these compounds demonstrated robust binding to CA-II (-8.4 and -8.7 kcal/mol, respectively). Protein-ligand interaction profiler analysis elucidated key stabilizing interactions, including hydrogen bonds with Thr199 and His64 in CA-II and hydrophobic contacts within the SV2A binding pocket. MD simulations confirmed structural stability of the protein-ligand complexes, evidenced by equilibrated RMSD trajectories (0.2-0.3 nm). MM-GBSA calculations substantiated the thermodynamic favourability of these interactions, with binding free energies for top candidates significantly exceeding reference compounds. These findings establish an in silico framework for prioritizing Bacopa monnieri phytoconstituents as computationally predicted dual-target candidates, highlighting their potential relevance for seizure management, with the possibility of improved efficacy through simultaneous modulation of distinct pathophysiological mechanisms. All findings are based solely on in silico analyses and require experimental validation.