A Comprehensive Theoretical Study of Anti-Epileptic Drug Design: DFT, TD-DFT, and Molecular Docking Approach.

Background: Epilepsy is a chronic neurological disease that affects around 50 million people globally. To cure this disorder, different antiepileptic drugs have been studied via computational approaches.

Methods: Density functional theory (DFT) and time-dependent-density functional theory (TDDFT) are employed to investigate the optoelectronic, photodynamic, and structural properties of antiepileptic drugs (EP1-EP5). The B3LYP/6-311 G (d, p) was used for the computational simulations study. Further comparisons with reference drug phenobarbital (R) and (EP1-EP5) drugs, several geometrical variables, including frontier molecular orbitals (FMOs), excitation energy, hole-electron overlap, density of states, binding energy, molecular electrostatic potential, transition density matrix, and density of states were performed.

Results: Compared to R with antiepileptic drugs AEDs (EP1-EP5) exhibited a bathochromic shift of the absorption spectrum, lower excitation energies, and comparable binding energies. The findings showed that the antiepileptic drugs had significantly lower HOMO-LUMO energy gaps (Eg = 1.89-1.98 eV), pointing to their higher charge-directing behavior from HOMO to LUMO. The EP5 molecule exhibited excellent HOMO (-7.17 eV), LUMO (-2.80 eV), lowest energy band gap (4.37 eV), and boosted DOS results, which strengthens the drug-protein interaction.

Conclusion: EP5 exhibited the enhanced performance due to the presence of the electron withdrawing group in the acceptor region, extended conjugation, and better charge transference could be the best drug efficiency. During molecular docking, the robust interactions in EP5 with the antiepileptic proteins (4EY7 and 7SK2) showed an excellent structural template among the designed drugs. Among them, EP5 has better structural properties as an antiepileptic drug for future drug discovery.